Spontaneous regression occurs in some human malignant melanomas and basal cell carcinomas (BCCs). We have compared the cellular infiltrate in regressing and nonregressing tumors in order to analyze the mechanism by which regression occurs. Regressing primary melanomas and BCCs were infiltrated with a larger number of CD4⁺, but not CD8⁺, T lymphocytes than were seen in nonregressing tumors. The number of interleukin 2 receptor-positive (early activation marker) but not transferrin receptor-positive (intermediate activation marker) T cells was increased, indicating that the infiltrating T cells were activated. Large numbers of Langerhans cells, macrophages, and other class II major histocompatibility complex (MHC)-expressing cells were present but were not increased in the regressing tumors. There were no detectable B lymphocytes, and the regressing tumor cells displayed levels of HLA-DR expression similar to those of the nonregressing tumors. Comparison of squamous cell carcinoma (SCCs) with keratoacanthomas (KAs), which are likely to be a spontaneously regressing form of SCC, also showed increased infiltration of activated CD4⁺, but not CD8⁺, T cells within the KA. A murine ultraviolet (UV)-induced squamous tumor that spontaneously regresses when transplanted into immunocompetent syngeneic mice was also infiltrated with increased numbers of activated CD4⁺, but not CD8⁺, T cells prior to and during rejection. These results indicate that spontaneous regression of human skin tumors is likely to be immunologically mediated, and that CD4⁺ T lymphocytes seem to mediate this regression.