The first evidence of an association between HPV and non-melanoma skin cancer comes from patients with epidermodysplasia verruciformis (EV). EV is a rare heritable disease characterized by cutaneous warts that display not only a high rate of progression to squamous cell carcinoma on sun-exposed sites, but also a strong predisposition to infection by β-HPVs, for which HPV 5 and 8 predominate. Two EV genes (EVER1 and EVER2) have been identified, and we tested the hypothesis that variation in the EVER2 gene (rs7208422) is related to seropositivity to HPV (of the genus β types) and risk of squamous cell carcinoma in a population-based case-control study of SCC (n = 239 cases and 432 controls). Among controls, variant genotype was associated with β-HPV seropositvity (OR = 2.3, 95%CI = 1.2–4.3), specifically HPV5 or 8 seropositivity (OR = 2.4, 95%CI = 1.1–5.1) and seropositivity for multiple β-HPV types (OR = 2.7, 95%CI = 1.1–6.6). Furthermore, variant genotype was also related to SCC risk [adjusted OR for homozygous variant versus homozygous wild type for the EVER2 polymorphism 1.7, 95% CI 1.1–2.7]. These data provide evidence for a role of genetic variation in the EVER2 gene in β-HPV infection and risk of SCC, shedding light on the link between HPVs and skin cancers. © 2008 Wiley-Liss, Inc.