In order to elucidate the role of myofibroblasts in tumor development, we compared fibroblastic reactions and their implications in the immune response in progressive and regressive rat colorectal-tumor models. Immunohistochemical analyses revealed that T lymphocytes and monocytes/macrophages were found outside progressive tumors that were surrounded by a large sheath of myofibroblasts. In vitro experiments using fibroblast- vs. myofibroblast-containing collagen gels showed that the mechanical properties of these tumor-activated myofibroblasts prevent penetration of T lymphocytes and macrophages within tumor nodules. These results indicate that tumor-activated myofibroblasts may prevent physical contact between cancer-cells and immune cells, an essential phenomenon for effective destruction of cancer cells. Successful immunotherapy against cancer should therefore include complementary treatments against these tumor-associated fibroblasts.