The role that cell-mediated immune responses play during cutaneous carcinogenesis has received little attention. In this study, we evaluated the contribution of CD4+ and CD8+ T cells in C3H/HeN mice that were subjected to a two-stage 7,12-dimethylbenz(a)anthracene (DMBA) initiation, 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion skin carcinogenesis protocol. In CD8 knockout (CD8-/-) mice, allergic contact hypersensitivity to DMBA was reduced compared with wild-type (WT) C3H/HeN mice. On the other hand, CD4 knockout (CD4-/-) mice developed an exaggerated contact hypersensitivity response. CD4+ T cells from DMBA contact-sensitized mice preferentially produced interleukin 4 (IL-4), IL-10, and IL-17; CD8+ T cells, on the other hand, secreted IFN-γ. When CD4-/-, CD8-/-, and WT mice were subjected to a standard two-stage DMBA/TPA cutaneous carcinogenesis protocol, the percentage of mice with tumors was much greater (P < 0.001) in CD8-/- mice than in WT mice. In contrast, the percentage of tumors was significantly less (P < 0.001) in CD4-/- mice than in WT mice. Similar results were obtained when the data were evaluated as the number of tumors per mouse. These findings indicate that (a) CD8+ T cells are the predominant effector cells in allergic contact hypersensitivity to DMBA and that CD4+ T cells have an inhibitory role and (b) the development of CD8+ T cells plays a protective role in skin tumor development whereas CD4+ T cells have the opposite effect. Manipulation of T-cell subpopulations that are induced by carcinogenic chemicals, like DMBA, could be a means of preventing skin cancers caused by these agents. ©2008 American Association for Cancer Research.