The mitogenic response to phytohemagglutinin (PHA) by spleen cells from C3H/HeJ mice bearing either autochthonous tumors or early-generation transplanted spontaneous mammary tumors was depressed in some, but not all, tumor-bearing animals. T-cell hyporesponsiveness in both groups was associated with the larger (more rapidly growing) tumor burdens. The growth patterns of the transplanted tumors and the associated PHA-induced responses were not affected by the initial tumor cell dose or by the number of in vivo passages of the tumor cell lines. Suppressor cell activity was detected in the hyporesponsive spleens of mice bearing transplanted tumors. Depletion of phagocytic macrophages, rayon wool-adherent cells, or theta-positive lymphocytes did not remove the suppressor cell activity. The mitogenic response of some but not all hyporesponsive spleens from autochthonous tumor bearers was restored after removal of phagocytic macrophages. The results demonstrated the heterogeneity of the factor(s) influencing non-specific T-cell reactivity in animals bearing spontaneous mammary tumors. Furthermore, our data suggest that nonspecific immunosuppression does not precede spontaneous tumor appearance but is probably a late result of rapid, extensive tumor growth.