Repeated application of the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA) to the skin of mice previously treated with an initiating dose of the carcinogen 7,12-dimethylbenz[a] anthracene has been shown to lead to an increased incidence of papilloma. The studies presented here describe a modified murine two-stage carcinogenesis model in which a single subcutaneous administration of the carcinogen 3-methylcholanthrene (3-MC) is followed by multiple applications of TPA administered subcutaneously or intraperitoneally. TPA was observed to act as a promoter under these conditions when given either subcutaneously or intraperitoneally. When a carcinogenic dose of 3-MC was administered (0.5 mg/mouse) followed by regular treatment with TPA (10 micrograms/mouse) the percent of tumor-bearing mice increased and the length of time until tumors developed significantly shortened. At a subcarcinogenic dose of 3-MC (0.025 mg/mouse), repeated treatment with TPA led to tumor development whereas no tumors were observed in mice not treated with TPA. All tumors were found to be fibrosarcomas. Thus, TPA is capable of acting as a systemic promoter of mesenchymally derived tumors.