We studied 51 cervical carcinomas, among them 25 squamous-cell carcinomas (SCC) and 26 cervical adenocarcinomas (AdCa), and 40 vulvar SCC for the presence of HPV and mutant p53. HPV was detected by PCR, and p53 alterations by temperature-gradient gel electrophoresis/direct sequencing and immunohistochemistry. HPV, mostly type 16/18, was found in 80.4% of the cervical tumors (92.0% of the SCC and 69.2% of the AdCa), but in only 27.5% of vulvar carcinomas. In contrast, p53 mutations were found in 7.8% and 52.5% of cervical and vulvar tumors respectively. Mutant p53 occurred in pre-invasive vulvar lesions, indicating that this oncogenic factor is involved early in carcinogenesis. Further analysis of recurrent/metastatic lesions of 9 cervical and 14 vulvar tumors also showed remarkable differences: in cervical cancer, HPV was persistent, and p53 mutations absent, whereas in vulvar tumors, HPV was mostly absent or not persistent, and the p53 mutation rate was very high (78.6%). These observations suggest that HPV persistence is an important event for the evolution and maintenance of cervical cancer, whereas for vulvar cancers p53 mutation and not HPV activity is a central oncogenic event.