Ultraviolet radiation of mouse skin leads to epidermal hyperplasia, inflammation, and subsequent tumor development. In this study we determined to what extent the cell cycle machinery is altered during epidermal proliferation after ultraviolet B radiation. A minimal erythema dose, 90 mJ per cm2, increased the protein expression of the G1 phase cyclins, cyclin D1 and E, by 12 h. The majority of epidermal cells entered S phase between 18 and 24 h as determined by 5'-bromo-2'-deoxyuridine incorporation, proliferating cell nuclear antigen, and cyclin A immunohistochemistry. An increase in cyclin-dependent kinase 2 (cdk-2) protein expression occurred after 12 h, but no changes in cdk-4 or cdk-6 protein levels were observed. The increase in cyclin D1, E, and A protein expression was associated with an increase in cyclin D1-cdk-4, cyclin E-cdk-2, and cyclin A-cdk-2 complex formation. p53 protein expression was elevated through 48 h, and the cdk inhibitor protein p21(Cip1/WAF1) was elevated 6-fold to 7.5-fold between 12 and 24 h. The elevated p21(Cip1/WAF1) protein contributed to an enhanced association with cdk-2 and cdk-4 at 3-24 h and 6-24 h post-ultraviolet B irradiation, respectively. These data indicate that 90 mJ per cm2 of ultraviolet B irradiation induces a DNA damage response, by increasing p53 and p21(Cip1/WAF1) protein expression, but also induces a rapid and sustained increase in S phase by 18 h.