Several years after transplantation, renal transplant recipients develop numerous cutaneous squamous cell carcinomas (SCC), in which human papillomaviruses (HPV) may be detected. Alterations in c-myc, c-Ha-ras, and p53 genes were studied in 34 SCC, in correlation with the presence of HPV. In situ hybridization (ISH) and polymerase chain reaction (PCR) showed that many SCC contained several HPV types infecting different foci of epithelial cells. Using Southern blot and ISH, c-myc and/or c-Ha-ras gene amplification was detected in 7/13 SCC tested. With PCR and oligoprobe hybridization, a GGC -> GAC mutation was found at codon 12 of c-Ha-ras gene in 1/21 SCC tested, while no mutation was detected at codon 61. Using immunohistochemistry, p53 protein expression was detected either along the basal cell layer or spotted in foci of basal cells. Our results show an abnormal distribution of HPV types in SCC from renal transplant recipients, and alterations of c-myc, c-Ha-ras, and p53 genes without any direct link with the presence of any studied HPV type. Thus, viral infection and oncogene activation may represent factors involved in the etiology of skin SCC from transplant recipients.