OBJECTIVE: To determine whether human papillomavirus (HPV) type 16 affects survival in oral squamous cell carcinoma. STUDY DESIGN: Two hundred fifty-four patients diagnosed with primary oral cancer were studied for survival in relation to tumor HPV type 16 status. Kaplan-Meier analysis and Cox proportional hazard models were used to assess survival and estimate hazard ratios adjusted for potential confounders. RESULTS: HPV type 16 DNA was detected in 15.1 % of tumors. HPV 16 positive patients had significantly reduced all-cause mortality (hazard ratio (HR) estimates = 0.34,95% Cl = 0.14,0.83) and disease-specific mortality (HR = 0.17, 95% Cl = 0.04, 0.76) compared with HPV 16 negative patients after adjustment for age, stage, treatment, smoking, alcohol, education, and comorbid disease. CONCLUSIONS: The presence of HPV type 16 DNA is independently associated with a favorable prognosis in patients with oral squamous cell carcinoma. CLINICAL SIGNIFICANCE: Although HPV genotyping is currently not widely available, it may provide important prognostic information.