diff --git a/roles/separate_build_node/defaults/main/common.yml b/roles/separate_build_node/defaults/main/common.yml
index 52b5817..b019604 100644
--- a/roles/separate_build_node/defaults/main/common.yml
+++ b/roles/separate_build_node/defaults/main/common.yml
@@ -17,4 +17,17 @@ working_directories:
   - "{{ base_work_dir }}/castor/build_node"
   - "{{ base_work_dir }}/castor/build_node/mock_configs"
   - "{{ final_conf_dir }}"
+# s390x builds requirements from source without build isolation:
+# grpcio 1.58 setup.py needs pkg_resources (removed in setuptools 81),
+# git deps with PEP 621 metadata need setuptools>=61 (system one is 53
+# and satisfies a bare "<81" via --system-site-packages)
+build_node_s390x_build_requirements:
+  - "setuptools>=61,<81"
+  - "cython<3"
+  - "wheel"
+build_node_s390x_pip_environment:
+  GRPC_PYTHON_BUILD_SYSTEM_OPENSSL: "1"
+  GRPC_PYTHON_BUILD_SYSTEM_ZLIB: "1"
+  GRPC_PYTHON_BUILD_SYSTEM_CARES: "1"
+  GRPC_PYTHON_BUILD_EXT_COMPILER_JOBS: "1"
 ...
diff --git a/roles/separate_build_node/defaults/main/dnf.yml b/roles/separate_build_node/defaults/main/dnf.yml
index 6936131..26101b0 100644
--- a/roles/separate_build_node/defaults/main/dnf.yml
+++ b/roles/separate_build_node/defaults/main/dnf.yml
@@ -32,4 +32,10 @@ build_node_dnf_packages:
   - "ubu-keyring"
   - "xmlsec1-openssl-devel"
   - "rsyslog-logrotate"
+# s390x has no prebuilt wheels for some requirements (e.g. grpcio),
+# they are compiled against these system libraries
+build_node_s390x_dnf_packages:
+  - "c-ares-devel"
+  - "openssl-devel"
+  - "zlib-devel"
 ...
diff --git a/roles/separate_build_node/tasks/create_env.yml b/roles/separate_build_node/tasks/create_env.yml
index 2ae930b..33f66e5 100644
--- a/roles/separate_build_node/tasks/create_env.yml
+++ b/roles/separate_build_node/tasks/create_env.yml
@@ -49,12 +49,24 @@
   become_user: "{{ service_user }}"
   ansible.builtin.command: "{{ build_node_venv_directory }}/bin/pip install --upgrade pip"
 
+- name: Install s390x build requirements into virtualenv
+  become: yes
+  become_user: "{{ service_user }}"
+  ansible.builtin.pip:
+    name: "{{ build_node_s390x_build_requirements }}"
+    virtualenv: "{{ build_node_venv_directory }}"
+  when: ansible_facts['architecture'] == 's390x'
+  tags:
+    - update-env
+
 - name: Install requirements into virtualenv
   become: yes
   become_user: "{{ service_user }}"
   ansible.builtin.pip:
     requirements: "{{ build_node_requirements_path }}"
     virtualenv: "{{ build_node_venv_directory }}"
+    extra_args: "{{ '--no-build-isolation' if ansible_facts['architecture'] == 's390x' else omit }}"
+  environment: "{{ build_node_s390x_pip_environment if ansible_facts['architecture'] == 's390x' else {} }}"
   tags:
     - update-env
 ...
diff --git a/roles/separate_build_node/tasks/dnf.yml b/roles/separate_build_node/tasks/dnf.yml
index 39841e1..afef204 100644
--- a/roles/separate_build_node/tasks/dnf.yml
+++ b/roles/separate_build_node/tasks/dnf.yml
@@ -35,4 +35,13 @@
       - buildnode
       - "{{ powertools_repository_name }}"
     update_cache: yes
+
+- name: Install s390x build dependencies for Python packages
+  become: yes
+  ansible.builtin.dnf:
+    name: "{{ build_node_s390x_dnf_packages }}"
+    state: latest
+    enablerepo:
+      - "{{ powertools_repository_name }}"
+  when: ansible_facts['architecture'] == 's390x'
 ...