SSIN mice are considerably more sensitive to the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) in two-stage skin carcinogenesis protocols than are most other strains and stocks of mice. Experiments were performed to determine whether there was an immunological basis for this sensitivity. SSIN mice were haplotyped and found to be H-2q. T cells represented approximately 31% of the splenic cellularity of non-treated SSIN mice, but approximately 44% in BALB/c, C57BL/6, B6C3F1 and SENCAR mice. Splenic CD4+/CD8+ T cell ratios were approximately 4.2, 2.9, 2.4, 1.8 and 1.7 in SSIN, SENCAR, BALB/c, B6C3F1 and C57BL/6 mice, respectively. The unusually high ratio in SSIN spleens was the consequence of reductions in CD8+ T cells. The ratio of CD4+/CD8+ T cells in SSIN thymocytes was similiar to that measured in the spleen. The splenic cytotoxic T lymphocyte (CTL) activities of the various murine strains inversely correlated with their splenic CD4+/CD8+ ratios and their sensitivities in two-stage skin carcinogenesis protocols. Repeated in vivo topical treatment of SSIN mice with TPA caused significant decreases in splenic T cell contents, but affected neither the splenic CD4+/CD8+ T cell ratio nor the development of a CTL response upon allogeneic tumor challenge. SSIN mice also had very low splenic natural killer cell activities. Furthermore, relative to the other strains of mice, SSIN mice were poor responders upon alloantigen challenge in mixed lymphocyte response assays. These findings demonstrate that SSIN mice differ markedly from other murine stocks and strains in their splenic lymphocyte composition and in their abilities to mount some MHC-restricted and non-restricted immunosurveillance processes.