Epidermodysplasia verruciformis (EV) is a rare autosomal recessive genodermatosis associated with a high risk of skin carcinoma. EV results from an abnormal susceptibility to infection by specific human papillomavirus (HPV) genotypes (beta-papillomaviruses) which include the potentially oncogenic HPV5. EV-specific HPVs are considered as harmless for the general population. EV was recently found to be caused by invalidating mutations in two adjacent, related, novel genes, EVER1/TMC6 and EVER2/TMC8. EVER genes encode transmembrane proteins located in the endoplasmic reticulum, which are likely to function as modifiers of ion transporters or channels and to be involved in signal transduction. It was proposed that EV was a primary defect of innate immunity. Our hypothesis is that EVER proteins act as restriction factors for EV-specific HPVs in keratinocytes, and that EV represents a primary deficiency of intrinsic immunity against certain papillomaviruses.