Recombinant DNA-derived murine gamma-interferon (rMuIFN-gamma) was tested in the murine skin multistage carcinogenesis model as a modulator of 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion. Female SENCAR mice were topically initiated with 7,12-dimethylbenz(a)anthracene and promoted twice weekly with TPA for 20 weeks. Intraperitoneal administration of rMuIFN-gamma 1 day prior to TPA treatment affected neither the kinetics of papilloma development nor the percentage of mice that developed tumors. However, papilloma multiplicities could be either inhibited or increased depending upon the dose of rMuIFN-gamma. Papilloma multiplicities for mice receiving 100, 500, 1000, and 5000 units of rMuIFN-gamma were 184, 122, 105, and 84% of TPA control values, respectively. In contrast, twice weekly i.p. treatments of 7,12-dimethylbenz(a)anthracene initiated mice with only rMuIFN-gamma for 20 weeks did not promote the development of any tumors. Consequently, TPA functioned as a copromoter in those situations in which combined TPA and IFN-gamma treatments elevated papilloma multiplicities. Collectively, the current study demonstrates that rMuIFN-gamma can systemically modulate TPA-dependent promotion in mouse skin.