Epidemiological studies have consistently demonstrated a decrease in the risk of esophageal squamous cell carcinoma (SCC) associated with higher fruit and vegetable intake, although the association has been examined predominantly in case–control studies. Here, we conducted a population-based prospective cohort study among middle-aged Japanese men. Lifestyle characteristics were investigated using a self-administered questionnaire, which included a validated food frequency questionnaire with 138 food and beverage items. We followed a total of 38,790 men aged 45–74 years. A Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for esophageal SCC, with adjustment for potential confounders. During 297,651 person–years of follow-up, a total of 116 men were newly diagnosed with esophageal SCC. An increase in consumption of total fruit and vegetables by 100 grams per day (g/day) was associated with an 11% decrease in the incidence of esophageal SCC (95% CI: 1–21%). In particular, a higher intake of cruciferous vegetables was associated with a significant decrease in risk (HR per 100 g/day: 0.44; 95% CI: 0.23–0.82). Stratified analyses revealed that the beneficial effect of fruits and vegetables was not able to completely offset the harmful effect of tobacco and alcohol. Our findings provide further evidence for the protective role of fruits and vegetables in the development of esophageal SCC. To effectively reduce the burden of this disease, however, priority should be placed on smoking and drinking cessation. Finally, cruciferous vegetables deserve further investigation as foods possibly effective in the prevention of esophageal SCC. © 2008 Wiley-Liss, Inc.