Previously we have shown that a single subcarcinogenic dose of ionizing radiation followed by 60 wk of 12-O-tetradecanoylphorbol-13-acetate (TPA) leads to the formation of squamous cell carcinoma in Sencar mice. Our previous results also indicate that TPA pretreatment prior to irradiation results in an overall increase in total tumor incidence, including both epidermal and nonepidermal tumors (D. R. Jaffe and G. T. Bowden, Radiat. Res., 106: 156-165, 1986). These studies have been expanded in CD-1 mice to further investigate the effect of the proliferative state of the skin prior to irradiation and the promotion duration after irradiation on tumor incidence. To examine the influence of the proliferative state of the skin, 17 nmol of TPA were applied to one-half of the mice 24 h prior to irradiation. The skin was irradiated using 4 MeV X-rays at a dose rate of 0.31 Gy/min. Animals received a single dose of X-rays at 0.5 or 11.25 Gy followed by twice weekly applications of TPA (8 nmol). The animals were then promoted for either 10 or 60 wk. All animals that were promoted with TPA for the same duration had a similar incidence of papillomas regardless of radiation or TPA pretreatment. Increasing the promotion duration did not significantly alter the incidence of squamous cell carcinomas at either initiation dose. At the lower initiation dose only animals that were promoted for 60 wk developed squamous cell carcinomas. TPA pretreatment at the higher dose resulted in a slight decrease in tumor incidence; however, this was not statistically significant. The incidence of basal cell carcinomas was dose dependent and appeared to be independent of TPA promotion. These data support our earlier findings that radiation can act as a weak initiator of squamous cell carcinomas and induce basal cell carcinomas in mouse skin.