OBJECTIVE The aim of this study was to examine human papillomavirus 16/18 infection incidence and p53 alteration in oral squamous cell carcinoma and to determine whether a correlation existed between HPV infection incidence and p53 alteration in this disease. METHODS A series of 60 oral tissues (40 oral squamous cell carcinomas, 20 normal oral mucosas) was studied by polymerase chain reaction (PCR) to detect HPV 16 and 18 infection, and was studied by single strand conformation polymorphism (SSCP) and immunohistochemistry (IHC) to detect p53 mutation and accumulation, respectively. RESULTS HPV sequences were detected in 29 of 40 (72.5%) tumor specimens. A higher incidence (P = 0.037) of HPV 16/18 infection was observed in oral squamous cell carcinomas than in normal oral mucosas. Altered p53, either in genetic sequence or protein overexpression, was observed in 18 of 40 (45%) oral squamous cell carcinomas. Eleven of the 29 HPV-positive tumors contained observed alterations in either p53 protein expression or DNA sequence. No significant correlation (P = 0.145) was observed between HPV infection and p53 alteration. CONCLUSIONS These data suggest that HPV16/18 infection and/or p53 alterations are associated with oral squamous cell carcinoma. No inverse correlation exists between oncogenic HPV infection and p53 alteration.