TP53 mutations were analyzed in 35 human papillomavirus (HPV) type 16 DNA-positive cancers of the oral cavity and oropharynx and in 35 HPV DNA-negative cancers matched by subsite, country, sex, age, and tobacco and alcohol consumption. Wild-type TP53 was found more frequently in cancer specimens that contained HPV16 DNA than in those that did not. All 14 HPV16 DNA-positive cancers in HPV16 E6 antibody-positive patients contained wild-type TP53, compared with 50% of corresponding HPV DNA-negative cancers (matched odds ratio, infinity; 95% confidence interval, 1.4- infinity ). In contrast, for HPV16 DNA-positive cancers in E6-negative patients, wild-type TP53 frequency was similar to that in corresponding HPV DNA-negative cancers (matched odds ratio, 1.0; 95% confidence interval, 0.2-5.4). TP53 inactivation is a major mechanism of HPV-related carcinogenesis in the oral cavity and oropharynx. The role of HPV in cancers also containing TP53 mutations remains to be clarified.