Renal transplant recipients are prone to numerous benign and malignant skin lesions. Previous work in the authors' laboratory has determined that the human papillomavirus may be the viral aetiology of these skin lesions. The p53 tumor-suppressor gene is the most frequently mutated gene in a wide range of human cancers. Here the authors describe an immunohistochemical study to evaluate the expression of p53 in benign and malignant skin lesions from renal transplant recipients and immunocompetent patients with skin cancer. The effect of p53 mutations on the expression patterns observed were examined by polymerase chain reaction-single strand conformation polymorphism analysis and direct cycle sequencing. The expression of the p53-regulated cyclin-dependant kinase inhibitor p21Waf1/Cip1 and Mdm2 was also examined in p53-positive cells. The expression of p53 in benign and malignant lesions was found to be markedly different. p53 was expressed in only 40% (6/15) of viral warts analyzed. The expression was confined to the basal layer both in the lesion and in adjacent normal skin, and the level of expression was low and only in a small number of cells (<10%). Of the cutaneous squamous cell carcinomas analyzed, 60% (9/15) showed p53 expression. Two different patterns of expression were observed. Basal layer expression in both the invasive tumor and adjacent normal skin was observed in 50% of the p53-positive squamous cell carcinomas; in the remaining 50%, p53 was expressed diffusely throughout the invasive tumor and in the basal layer of adjacent normal skin. The level of expression was high and in a large number of cells. Polymerase chain reaction-single strand conformation polymorphism analysis revealed that only one of the squamous cell carcinomas expressing p53 harbored a p53 mutation and that the accumulated p53 in the remaining tumors was wild type. No Mdm2 or p21Waf1/Cip1 expression was detected in the p53-positive squamous cell carcinomas, indicating that although the accumulated p53 is stable, it does not function effectively as a transcriptional activator. This represents a novel p53 phenotype in cutaneous squamous cell carcinoma. In addition, no correlation was seen between the presence and absence of human papillomavirus and p53 expression.