A series of 120 biopsies from benign (verruca vulgaris and keratoacanthoma), premalignant (actinic keratosis and extragenital Bowen's disease) and malignant (squamous cell carcinoma) skin lesions were studied immunohistochemically for the expression of cell-cycle proteins p53, p21 (WAF-1), PCNA and Ki-67. The presence of human papillomavirus (HPV) DNA in these samples had been analysed previously using in situ hybridization (ISH) and PCR. Moderate to intense expression of both PCNA and Ki-67 was present in most of the lesions studied. PCNA staining was extensive in the epidermis underneath the layers where abundant HPV DNA staining was shown in HPV DNA-positive verrucas. In keratoacanthomas, p21 and PCNA expression remained low, despite intense p53 expression. In actinic keratosis, only half of the specimens showed overexpression of p53 associated with moderate or intense expression of PCNA. In extragenital Bowen's lesions, all these cell-cycle markers were overexpressed, but in squamous cell carcinomas, they were heterogeneously expressed and showed no correlation with tumour differentiation. Our results suggest a mechanism by which HPV can reactivate the host genes (leading to cell proliferation) to support its own DNA replication. Also p21 might start keratinocyte differentiation in areas where HPV DNA replication starts. Cell proliferation remained active in actinic keratosis and Bowen's lesions, emphasizing the precancer character of these lesions in contrast with the benign nature of keratoacanthoma and verruca vulgaris.