We examined the effects of hair cycle phase on basal cell carcinoma (BCC) tumorigenesis induced by radiation in mice lacking one Patched allele (Ptc1^neo67/+). Our results show that Ptc1^neo67/+ mouse skin irradiated in early anagen is highly susceptible to tumor induction, as a 3.2-fold incidence of visible BCC-like tumors was observed in anagen-irradiated compared with telogen-irradiated mice. Microscopic nodular BCC-like tumors were also enhanced by irradiation during active hair-follicle growth phases. Interestingly, histologic examination of the tumors revealed a qualitative difference in BCC tumorigenesis depending on hair growth phase at the time of exposure. In fact, in addition to typical BCC-like tumors, we observed development of a distinct basal cell tumor subtype characterized by anti–cytokeratin 14 and anti–smooth muscle actin reactivity. These tumors showed relatively short latency and rapid growth and were strictly dependent on age at irradiation, as they occurred only in mice irradiated in early anagen phase. Examination of anatomic and immunohistochemical relationships revealed a close relation of these tumors with the follicular outer root sheath of anagen skin. In contrast, there are strong indications for the derivation of typical, smooth muscle actin–negative BCC-like tumors from cell progenitors of interfollicular epidermis. These results underscore the role of follicular bulge stem cells and their progeny with high self-renewal capacity in the formation of basal cell tumors and contribute to clarify the relationship between target cell and tumor phenotype in BCC tumorigenesis induced by radiation. (Cancer Res 2006; 66(13): 6606-14)