Mutations of the p53 gene have been implicated as an important factor in the pathogenesis of ultraviolet light induced skin cancers. To examine the role of p53 in skin carcinogenesis, we observed the development of skin cancers in homozygous p53-deficient (-/-) mice and wild-type p53 (+/+) mice, after chronic ultraviolet B (290-320 nm) exposure. At a dose of 2 J per m2 per s of ultraviolet B for 30 min three times per week, all p53-/- mice developed skin tumors by week 12. All the p53-/- mice developed multiple tumors by week 16. The majority of the tumors occurred on the ears. None of the p53+/+ mice developed skin tumors after 17 wk of UV exposure. Ten p53-/- tumors were examined histologically: five invasive squamous cell carcinomas, four squamous cell carcinomas in situ, and one actinic keratosis. p53-/- mice have a short life-span due to internal tumors or a deficiency in the immune system; however, ultraviolet B exposure did not significantly reduce the life-span of p53-/- mice. These results demonstrate that loss of wild-type p53 function shortens the latent period and predisposes the animals to the development of squamous cell carcinomas after ultraviolet irradiation.