diff --git a/R/rxp_io.R b/R/rxp_io.R
index 36c01de..49bb8aa 100644
--- a/R/rxp_io.R
+++ b/R/rxp_io.R
@@ -644,12 +644,31 @@ rxp_jl_file <- function(...) rxp_file("Jl", ...)
 #' @return A list with elements: `name`, `snippet`, `type`, `additional_files`,
 #'   `nix_env`.
 #' @noRd
-rxp_common_setup <- function(out_name, expr_str, nix_env, direction) {
+rxp_common_setup <- function(
+  out_name,
+  expr_str,
+  nix_env,
+  direction,
+  env_var = NULL
+) {
   expr_str <- gsub("\"", "'", expr_str)
   base <- sanitize_nix_env(nix_env)
 
+  # Always set RETICULATE_AUTOCONFIGURE=0 to prevent reticulate from
+  # modifying PYTHONPATH in Nix's hermetic build environment
+  default_env <- c(RETICULATE_AUTOCONFIGURE = "0")
+
+  # Merge with user-provided env_var if present (user values take precedence)
+  if (!is.null(env_var) && length(env_var) > 0) {
+    env_var <- c(default_env[!names(default_env) %in% names(env_var)], env_var)
+  } else {
+    env_var <- default_env
+  }
+
+  env_exports <- build_env_exports(env_var)
+
   r_command <- build_transfer_command(out_name, expr_str, direction)
-  build_phase <- build_reticulate_phase(r_command)
+  build_phase <- build_reticulate_phase(r_command, env_exports)
 
   snippet <- make_derivation_snippet(
     out_name = out_name,
@@ -665,7 +684,8 @@ rxp_common_setup <- function(out_name, expr_str, nix_env, direction) {
       snippet = snippet,
       type = paste0("rxp_", direction),
       additional_files = "",
-      nix_env = nix_env
+      nix_env = nix_env,
+      env_var = env_var # Store for potential inspection/debugging
     ),
     class = "rxp_derivation"
   )
@@ -704,9 +724,10 @@ build_transfer_command <- function(out_name, expr_str, direction) {
 #' @param r_command Character R command
 #' @return Character build phase
 #' @noRd
-build_reticulate_phase <- function(r_command) {
+build_reticulate_phase <- function(r_command, env_exports = "") {
   sprintf(
-    "export RETICULATE_PYTHON=${defaultPkgs.python3}/bin/python\n       Rscript -e \"\n         source('libraries.R')\n%s\"",
+    "# Clear any inherited PYTHONPATH\n       unset PYTHONPATH || true\n       # Dynamically determine Python version and set PYTHONPATH\n       PYTHON_VERSION=$(${defaultPkgs.python3}/bin/python3 -c 'import sys; print(f\"{sys.version_info.major}.{sys.version_info.minor}\")')\n       export PYTHONPATH=${defaultPkgs.python3}/lib/python$PYTHON_VERSION/site-packages\n       export RETICULATE_PYTHON=${defaultPkgs.python3}/bin/python\n       export RETICULATE_AUTOCONFIGURE=0\n       %sRscript -e \"\n         source('libraries.R')\n%s\"",
+    env_exports,
     r_command
   )
 }
@@ -718,14 +739,16 @@ build_reticulate_phase <- function(r_command) {
 #' @param expr Symbol, Python object to be loaded into R.
 #' @param nix_env Character, path to the Nix environment file, default is
 #'   "default.nix".
+#' @param env_var Named list of environment variables to set. RETICULATE_AUTOCONFIGURE=0
+#'   is set by default to prevent reticulate from modifying PYTHONPATH in Nix builds.
 #' @details `rxp_py2r(my_obj, my_python_object)` loads a serialized Python
 #'   object and saves it as an RDS file using `reticulate::py_load_object()`.
 #' @return An object of class `rxp_derivation`.
 #' @export
-rxp_py2r <- function(name, expr, nix_env = "default.nix") {
+rxp_py2r <- function(name, expr, nix_env = "default.nix", env_var = NULL) {
   out_name <- deparse1(substitute(name))
   expr_str <- deparse1(substitute(expr))
-  rxp_common_setup(out_name, expr_str, nix_env, "py2r")
+  rxp_common_setup(out_name, expr_str, nix_env, "py2r", env_var)
 }
 
 #' Transfer R Object into a Python Session
@@ -735,12 +758,14 @@ rxp_py2r <- function(name, expr, nix_env = "default.nix") {
 #' @param expr Symbol, R object to be saved into a Python pickle.
 #' @param nix_env Character, path to the Nix environment file, default is
 #'   "default.nix".
+#' @param env_var Named list of environment variables to set. RETICULATE_AUTOCONFIGURE=0
+#'   is set by default to prevent reticulate from modifying PYTHONPATH in Nix builds.
 #' @details `rxp_r2py(my_obj, my_r_object)` saves an R object to a Python pickle
 #'   using `reticulate::py_save_object()`.
 #' @return An object of class `rxp_derivation`.
 #' @export
-rxp_r2py <- function(name, expr, nix_env = "default.nix") {
+rxp_r2py <- function(name, expr, nix_env = "default.nix", env_var = NULL) {
   out_name <- deparse1(substitute(name))
   expr_str <- deparse1(substitute(expr))
-  rxp_common_setup(out_name, expr_str, nix_env, "r2py")
+  rxp_common_setup(out_name, expr_str, nix_env, "r2py", env_var)
 }
diff --git a/R/rxp_make.R b/R/rxp_make.R
index ad75388..6901c48 100644
--- a/R/rxp_make.R
+++ b/R/rxp_make.R
@@ -506,4 +506,4 @@ rxp_import_artifacts <- function(
   message("Importing store paths from ", archive_file)
   system2("nix-store", args = "--import", stdin = archive_file)
   message("Import completed")
-}
\ No newline at end of file
+}
diff --git a/man/rxp_py2r.Rd b/man/rxp_py2r.Rd
index b0dc5db..211c366 100644
--- a/man/rxp_py2r.Rd
+++ b/man/rxp_py2r.Rd
@@ -4,7 +4,7 @@
 \alias{rxp_py2r}
 \title{Transfer Python Object into an R Session}
 \usage{
-rxp_py2r(name, expr, nix_env = "default.nix")
+rxp_py2r(name, expr, nix_env = "default.nix", env_var = NULL)
 }
 \arguments{
 \item{name}{Symbol, name of the derivation.}
@@ -13,6 +13,9 @@ rxp_py2r(name, expr, nix_env = "default.nix")
 
 \item{nix_env}{Character, path to the Nix environment file, default is
 "default.nix".}
+
+\item{env_var}{Named list of environment variables to set. RETICULATE_AUTOCONFIGURE=0
+is set by default to prevent reticulate from modifying PYTHONPATH in Nix builds.}
 }
 \value{
 An object of class \code{rxp_derivation}.
diff --git a/man/rxp_r2py.Rd b/man/rxp_r2py.Rd
index b64af0c..2e7ab20 100644
--- a/man/rxp_r2py.Rd
+++ b/man/rxp_r2py.Rd
@@ -4,7 +4,7 @@
 \alias{rxp_r2py}
 \title{Transfer R Object into a Python Session}
 \usage{
-rxp_r2py(name, expr, nix_env = "default.nix")
+rxp_r2py(name, expr, nix_env = "default.nix", env_var = NULL)
 }
 \arguments{
 \item{name}{Symbol, name of the derivation.}
@@ -13,6 +13,9 @@ rxp_r2py(name, expr, nix_env = "default.nix")
 
 \item{nix_env}{Character, path to the Nix environment file, default is
 "default.nix".}
+
+\item{env_var}{Named list of environment variables to set. RETICULATE_AUTOCONFIGURE=0
+is set by default to prevent reticulate from modifying PYTHONPATH in Nix builds.}
 }
 \value{
 An object of class \code{rxp_derivation}.
diff --git a/tests/testthat/test-reticulate-config.R b/tests/testthat/test-reticulate-config.R
new file mode 100644
index 0000000..233c087
--- /dev/null
+++ b/tests/testthat/test-reticulate-config.R
@@ -0,0 +1,67 @@
+test_that("rxp_py2r sets RETICULATE_AUTOCONFIGURE=0 by default", {
+  # Mock user input
+  nix_env <- "default.nix"
+
+  # Default behavior
+  res <- rxp_py2r(
+    name = my_obj,
+    expr = py_obj,
+    nix_env = nix_env
+  )
+
+  expect_true(!is.null(res$env_var))
+  expect_equal(res$env_var[["RETICULATE_AUTOCONFIGURE"]], "0")
+
+  # Verify it appears in the snippet (indirectly validating build_reticulate_phase logic if it was simple string matching)
+  # But better to check the structured 'env_var' component we added.
+})
+
+test_that("rxp_r2py sets RETICULATE_AUTOCONFIGURE=0 by default", {
+  nix_env <- "default.nix"
+
+  res <- rxp_r2py(
+    name = py_obj,
+    expr = r_obj,
+    nix_env = nix_env
+  )
+
+  expect_true(!is.null(res$env_var))
+  expect_equal(res$env_var[["RETICULATE_AUTOCONFIGURE"]], "0")
+})
+
+test_that("User can override RETICULATE_AUTOCONFIGURE", {
+  nix_env <- "default.nix"
+
+  # Override to "1"
+  res_override <- rxp_py2r(
+    name = my_obj,
+    expr = py_obj,
+    nix_env = nix_env,
+    env_var = c(RETICULATE_AUTOCONFIGURE = "1")
+  )
+
+  expect_equal(res_override$env_var[["RETICULATE_AUTOCONFIGURE"]], "1")
+
+  # Override to empty string/something else
+  res_override2 <- rxp_r2py(
+    name = py_obj,
+    expr = r_obj,
+    nix_env = nix_env,
+    env_var = c(RETICULATE_AUTOCONFIGURE = "custom")
+  )
+  expect_equal(res_override2$env_var[["RETICULATE_AUTOCONFIGURE"]], "custom")
+})
+
+test_that("env_var merging works correctly with other variables", {
+  nix_env <- "default.nix"
+
+  res <- rxp_py2r(
+    name = my_obj,
+    expr = py_obj,
+    nix_env = nix_env,
+    env_var = c(OTHER_VAR = "foo")
+  )
+
+  expect_equal(res$env_var[["RETICULATE_AUTOCONFIGURE"]], "0")
+  expect_equal(res$env_var[["OTHER_VAR"]], "foo")
+})