The objective of the present study was to examine the association between human papillomavirus (HPV) infection and risk of developing oral cancer. The investigation followed a hospital-based case-control design. Cases consisted of newly diagnosed patients with squamous cell carcinoma of the oral cavity and oropharynx. Controls were frequency matched to cases on gender, age, and hospital. Subjects were interviewed to elicit information on putative risk factors. Oral exfoliated cells were tested for detection of HPV DNA by the PGMY09/11 polymerase chain reaction protocol. Serum antibodies against HPV 16, 18, and 31 viral capsids were detected using an immunoassay technique. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) of oral cancer according to HPV exposure variables. HPV DNA was detected in 19% of cases (14 out of 72), and 5% of controls (six out of 129). Among tonsil-related cancers (palatine tonsil and base of tongue) viral DNA was detected in 43% of cases (nine out of 21). The OR for tonsil-related cancers for high-risk HPV types was 19.32 (95%CI: 2.3-159.5), after adjustment for socio-demographic characteristics, tobacco, and alcohol consumption. The equivalent OR for HPV 16 seropositivity was 31.51 (95%CI: 4.5-219.7). The ORs of non-tonsillar oral cancers for high risk HPV DNA in oral cells and for seropositivity were 2.14 (95%CI: 0.4-13.0) and 3.16 (95%CI: 0.8-13.0), respectively. These results provide evidence supporting a strong causal association between HPV infection and tonsil-related cancers. The evidence for an etiologic link is less clear for non-tonsillar oral cancers.