Human papillomavirus-16 (HPV-16) is a risk factor for head and neck squamous cell carcinoma (HNSCC). HPV-positive cancers have distinct disease cofactors and improved survival following treatment. There is conflicting evidence of a protective association of fruit consumption with HNSCC. As HPV-related disease is clinically distinct, we investigated whether the association between fruit consumption and HNSCC risk was modified by exposure to HPV-16. We studied 270 cases and 493 controls with fruit intake information and known HPV-16 antibody status. Cases were identified at nine Boston-area medical facilities between 1999 and 2003. Controls were randomly selected from the greater population and frequency matched to cases by age, gender, and town of residence. Controlling for age, gender, race, smoking, alcohol, total energy intake, body mass index, and education, the seronegative individuals had a significantly lower risk of HNSCC with increasing total fruit consumption [odds ratio (OR)(tertile 2), 0.60; 95% confidence interval (95% CI), 0.38-0.95; OR(tertile 3), 0.57; 95% CI, 0.35-0.95] and specifically increasing citrus fruit consumption (OR(tertile 2), 0.61; 95% CI, 0.39-0.97; OR(tertile 3), 0.59; 95% CI, 0.37-0.96). However, among the seropositive, risk increased with greater fruit consumption (OR(tertile 2), 2.27; 95% CI, 0.92-5.58; OR(tertile 3), 1.40; 95% CI, 0.55-3.59) and citrus fruit consumption (OR(tertile 2), 3.35; 95% CI, 1.36, 8.24; OR(tertile 3), 3.15; 95% CI, 1.23-8.08). This interaction was statistically significant (P < 0.05), showing that fruit consumption was associated with a reduced HNSCC risk among HPV-16-seronegative individuals but an increased HNSCC risk among the HPV-16-seropositive individuals. These findings suggest that dietary factors dramatically alter the pattern of occurrence of HPV-associated HNSCC and show that viral-related disease is clinically and etiologically distinct.