Cutaneous squamous cell carcinoma (SCC), along with basal cell carcinoma (BCC), comprise the non- melanoma skin cancers (NMSC), the most common cancer in Caucasians, with more than 3,000,000 new cases diagnosed annually in the United States. NMSC, though not as often fatal as other cancers, is associated with high treatment costs at the national level, significant patient morbidity, and an increased risk of developing other cancers. Exposure to UV radiation is an established risk factor for NMSC, but despite public knowledge about the harms of sun exposure and protective effects of sunscreen, NMSC incidence rates continue to increase, emphasizing the critical need for identification of additional risk factors for NMSC that may better characterize individuals at high risk and aid in the development of novel prevention strategies. Accumulating evidence suggests that cutaneous human papillomavirus (HPV) infection may be a risk factor for developing NMSC. DNA from cutaneous HPV types in multiple genera has been detected in up to 50% of NMSC tissues from immuno-competent individuals. In addition, several case-control studies, including our own, have demonstrated statistically significant associations between NMSC and antibodies against cutaneous HPV types, presence of HPV DNA in eyebrow hair follicles or HPV DNA in normal skin samples. We also observed associations between SCC and another cutaneous virus, Merkel cell polyomavirus (MCV), with MCV DNA-positive cases having significantly higher MCV antibody levels than controls. Although the case-control data are highly compelling, causal associations between cutaneous papillomavirus and polyomavirus infections cannot be established in the absence of prospective data that clearly demonstrate the presence and persistence of the viral infections prior to the onset of NMSC tumors that are positive for the same virus types. We propose to conduct a prospective cohort study of individuals at risk for NMSC, obtaining multiple biospecimens for the measurement of cutaneous HPV and MCV infections, and following participants for up to four years, conducting full body skin exams for th detection of incident NMSC. Repeated measures of UV exposure will also be obtained to examine its role as an effect modifier of the association between viral infection and NMSC. We hypothesize that an increased risk of NMSC will be observed among individuals infected with cutaneous HPV (BCC and SCC) and MCV (SCC only), and that the same viral types persistent in normal tissues will be detected in the subsequent NMSC tumors. We also hypothesize that the risk of NMSC associated with cutaneous viral infections will be greater among those with higher levels of UV exposure. The proposed study would provide the critical temporal evidence needed to advance our understanding of these viruses as potential etiologic agents in NMSC. If these viral infections play a causal role in NMSC, novel strategies for NMSC primary prevention could be developed in the future.