To analyze the role of human papillomavirus (HPV) infection and c-myc and c-Ha-ras oncogene activation in cutaneous and mucosal lesions, serial frozen sections of 47 lesions from grafted recipients and 10 biopsies from non-immunosuppressed patients were examined. HeLa, CaSki, MCF7, Colo 320 and 3T3 cells, which contain various copy numbers of HPV DNA and/or c-myc gene, were used as controls. HPV, myc and ras oncogene DNAs were not detected in normal epithelia by in situ hybridization with biotinylated DNA probes. The amplification of ras oncogene was detected in 20/57 lesions. The amplification of myc oncogene was found in 14/57 lesions, 13 of which showed both myc and ras gene amplification. c-myc and/or c-Ha-ras DNA was more frequently amplified in cutaneous squamous cell carcinomas (8/14 cases) and anogenital papillomas (4/6 cases), than in common and plantar warts (3/14 cases) or actinic keratoses (2/10 cases). HPV DNA was detected in 26/57 biopsies. Oncogene amplification was codetected with HPV DNA in 10/26 lesions, each of them containing at least one potentially oncogenic HPV type (5,16 and/or 18). The amplification was also found in 11/31 cases in the absence of HPV DNA. No significant difference was observed in the detection of HPV or oncogene DNA between the lesions of transplant recipients and those of the non-immunosuppressed population. Viral antigen was detected in 17/55 lesions by indirect immunofluorescence; 5 of the positive biopsies showed ras oncogene amplification. Myc and ras p21 oncoproteins were respectively localized in the nuclei and on the membrane of epithelial cells by indirect immunofluorescence. A good correlation was observed between the amplification of oncogenes and the expression of oncoproteins. Our results favor the hypothesis of a cooperation between HPV infection and myc and ras oncogene activation in skin carcinogenesis.