Squamous head and neck cancers include cancers of the oral cavity, pharynx and larynx are the sixth leading cause of cancer mortality worldwide, resulting in more than 350,000 deaths annually. Intake of fruit and vegetables may protect against head and neck cancer incidence, although few prospective studies have examined this association. We investigated this relation in 490,802 United States participants of the NIH-AARP Diet and Health cohort using Cox proportional hazard models adjusted for potential confounders. During 2,193,751 person years of follow-up from 1995/1996–2000, 787 participants were diagnosed with head and neck cancer. We found an inverse association between total fruit and vegetable intake and head and neck cancer risk (per serving/day/1,000 calories, Hazard Ratio, 95% Confidence interval: 0.94, 0.89–0.99). In models mutually adjusted for fruit and vegetable intake, the association was stronger for vegetables (fifth vs. first quintile: 0.65, 0.50–0.85) than for fruits (fifth vs. first quintile: 0.87, 0.68–1.11). When further subclassified into botanical groups, those in the highest tertile of leguminosae (dried beans, string beans and peas, 0.80, 0.67–0.96), rosaceae (apples, peach, nectarines, plums, pears and strawberries, 0.60, 0.49–0.73), solanaceae (peppers and tomatoes, 0.82, 0.69–0.98) and umbelliferae (carrots, 0.73, 0.60–0.89) had decreased risk of head and neck cancer, but no significant associations were seen for 9 other botanical groups. Results from this large prospective observational study are consistent with previous case-control studies and support the hypothesis that total fruit and vegetable intake is associated with reduced risk of head and neck cancer. © 2007 Wiley-Liss, Inc.