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A widely applicable cancer prevention strategy would be a cost-effective approach to lessen the enormous burden of cancer. Enterically-released microencapsulated rapamycin (eRapa) extends lifespan in mice and delays or prevents cancer development, suggesting cancer prevention as a longevity mechanism. Rapamycin acts through inhibition of mechanistic target of rapamycin (mTOR), which has significant immune effects that are surprisingly little studied in cancer treatment or prevention. In naive mice, chronic eRapa significantly reduced Th1 (CXCR3 + ) cell numbers ( p = .03) and T cell interferon (IFN)- γ ( p = .04), increased Th17 (CCR6 + ) cell numbers ( p = .04) and T cell IL-17 ( p = .03), increased T cell IL-22 ( p = .02), and reduced immune suppressing regulatory T cells ( p βδ −/− and IFN- γ −/− mice (lacking all T cells or IFN- γ , respectively) were given eRapa or control, and skin tumors were induced with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) followed by the inflammatory promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA). eRapa reduced papilloma size in WT BL6 mice ( p = .02) versus controls, the first demonstration that oral rapamycin prevents inflammation-mediated neoplasia. eRapa also significantly reduced papillomas in βδ −/− mice ( p = .04) and increased papillomas in IFN- γ −/− mice ( p = .05). These data are consistent with the concept that eRapa protects from carcinogen-induced dermal carcinogenesis through a non-T cell, IFN- γ -dependent mechanism, which we suspect includes natural killer cells. We have also shown that eRapa prevents cancer in a variety of mouse cancer models, in which we are further studying immune mechanisms. Immune contributions from mTOR inhibitors in cancer prevention (and treatment) require more attention.