Background: There is probable evidence that some types of fruit and vegetables provide protection against many cancers. Objective: We hypothesized that fruit and vegetable intakes are inversely related to the incidence of total cancers among women and men aged >50 y. Design: We performed a prospective study among the cohort of the National Institutes of Health-AARP Diet and Health Study. We merged the MyPyramid Equivalents Database (version 1.0) with food-frequency-questionnaire data to calculate cup equivalents for fruit and vegetables. From 1995 to 2003, we identified 15,792 and 35,071 cancer cases in 195,229 women and 288,109 men, respectively. We used Cox proportional hazards models to estimate multivariate relative risks (RRs) and 95% CIs associated with the highest compared with the lowest quintile (Q) of fruit and vegetable intakes. Results: Fruit intake was not associated with the risk of total cancer among women (RRQ5 vs Q1 = 0.99; 95% CI: 0.94, 1.05; P trend = 0.059) or men (RRQ5 vs Q1 = 0.98; 95% CI: 0.95, 1.02; P for trend = 0.17). Vegetable intake was not associated with risk of total cancer among women (RRQ5 vs Q1 = 1.04; 95% CI: 0.98, 1.09; P for trend = 0.084), but was associated with a significant decrease in risk in men (RRQ5 vs Q1 = 0.94; 95% CI: 0.91, 0.97; P trend = 0.004). This significant finding among men was no longer evident when we limited the analysis to men who never smoked (RRQ5 vs Q1 = 0.97; 95% CI: 0.91, 1.04; P for trend = 0.474). Conclusions: Intake of fruit and vegetables was generally unrelated to total cancer incidence in this cohort. Residual confounding by smoking is a likely explanation for the observed inverse association with vegetable intake among men.