The risk of head and neck squamous cell carcinoma (HNSCC) associated with common human papillomavirus types has not been well defined. We conducted a case-control study of 1034 individuals (486 incident cases diagnosed with HNSCC and 548 population-based controls matched to cases by age, gender, and town of residence) in Greater Boston, MA. Sera were tested for antibodies to human papillomavirus (HPV)6, HPV11, HPV16, and HPV18 L1. HPV6 antibodies were associated with an increased risk of pharyngeal cancer [odds ratio (OR)=1.6, 1.0-2.5], controlling for smoking, drinking, and HPV16 seropositivity. In HPV16-seronegative subjects, high HPV6 titer was associated with an increased risk of pharyngeal cancer (OR=2.3, 1.1-4.8) and oral cancer (OR=1.9, 1.0-3.6), suggesting that the cancer risk associated with HPV6 is independent of HPV16. There was no association between smoking and alcohol use and HPV6 serostatus. Further, the risk of pharyngeal cancer associated with heavy smoking was different among HPV6-seronegative (OR 3.1, 2.0-4.8) and HPV6-seropositive subjects (OR=1.6, 0.7-3.5), while heavy drinking also appears to confer differing risk among HPV6-negative (OR 2.3, 1.5-3.7) and -positive subjects (OR=1.3, 0.6-2.9). There may be interactions between positive serology and drinking and smoking, suggesting that the pathogenesis of human papillomavirus in HNSCC involves complex interactions with tobacco and alcohol exposure.