Nonmelanoma skin cancers (NMSC) are among the most common malignancies in the world. Typically, these neoplasms grow slowly and are comparatively indolent in their clinical behavior. The most frequent molecular alterations implicated in the pathogenesis of these neoplasms involve genes known to be regulators of cell death including p53, Ha-ras and bcl-2. In order to evaluate the significance cell death deregulation during skin carcinogenesis, we generated a transgenic mouse model (HK1. bcl-2) using the human keratin 1 promoter to target the expression of a human bcl-2 minigene to the epidermis. Transgenic HK1. bcl-2 protein was expressed at high levels specifically in the epidermis extending from the stratum basale through the stratum granulosum. The epidermis of HK1. bcl-2 mice exhibited multifocal hyperplasia without associated hyperkeratosis and aberrant expression of keratin 6. The rate of proliferation was similar in HK1. bcl-2 and control epidermis although suprabasal BrdUrd incorporating cells were present only in HK1. bcl-2 skin. Keratinocytes from the HK1. bcl-2 mice were significantly more resistant to cell death induction by UV-B, DMBA, and TPA, compared to control keratinocytes. Furthermore, papillomas developed at a significantly greater frequency and shorter latency in the HK1. bcl-2 mice compared to control littermates following initiation with DMBA and promotion with TPA. Together these results support a role for bcl-2 in the pathogenesis of NMSC.