Exposure to solar ultraviolet (UV) radiation is believed to cause most human skin carcinomas. Despite the large body of evidence connecting UV exposure with skin cancer, the frequency and level of human exposure to repetitive doses of UV light will most likely continue for occupational and recreational reasons. By investigating the cellular response of keratinocytes to multiple, physiologically relevant doses of UV, we hope to better understand the processes involved in UV-induced skin cancer. In this study, we used a UV exposure model to investigate the cell-cycle response of keratinocytes exposed to multiple doses of UV-B/A radiation in which the UV-C component (wavelengths below 290 nm) had been filtered out. Our results indicated that exposure of asynchronous mouse keratinocytes to three doses of 200 J/m2 UV-B/A radiation at 30 min intervals produced an inhibition of DNA synthesis and S-phase arrest between 7 and 25 h after the last irradiation. The S-phase arrest was not due to a reduction in the level of cyclin E and A proteins but was accompanied by inhibition of cyclin-dependent kinase 2 (cdk2) activity. We observed a similar pattern of cdk2 inhibition induced by multiple UV-B/A irradiations in mouse embryo fibroblasts from p21WAF null mice, indicating that the inhibition of cdk2 was independent of p21WAF in these cells.