Inbred female C3Hf/HeN, murine mammary tumor virus-negative mice exposed to either UV light or benzo[a]pyrene (BP), were subjected to four different chronic immunosuppressive regimens to determine their effect on skin cancer development. The immunosuppressive agents were cyclophosphamide, methotrexate, cortisone, and heterologous antilymphocyte globulin. Because of an unexpectedly high morbidity and mortality of mice exposed to chronic immunosuppressive measures, the dosages were kept at a level that permitted them to survive but did not prolong allogeneic skin graft survival and lower antibody titers, nor did this level diminish proliferative responses of lymphocytes to mitogens or allogeneic lymphocytes. Nevertheless, the latency periods (time interval between beginning of medication and appearance of skin tumors) of tumors in mice exposed to immunosuppressant measures were significantly shortened in several groups of mice exposed to UV and subjected to cyclophosphamide, cortisone, or antilymphocyte globulin and mice exposed to BP and subjected to cortisone acetate. In 3 groups, spindle cell tumors (fibrosarcomas) shifted to squamous cell carcinomas. A suppressed immune function would not be regarded as the mechanism for the observed responses because immunosuppression was not detected in the experimental mice.