To examine the changes in intake of fruits and vegetables in relation to risk of obesity and weight gain among middle-aged women. Prospective cohort study with 12 y of follow-up conducted in the Nurses' Health Study. A total of 74,063 female nurses aged 38-63 y, who were free of cardiovascular disease, cancer, and diabetes at baseline in 1984. Dietary information was collected using a validated food frequency questionnaire, and body weight and height were self-reported. During the 12-y follow-up, participants tended to gain weight with aging, but those with the largest increase in fruit and vegetable intake had a 24% of lower risk of becoming obese (BMI> or =30 kg/m2) compared with those who had the largest decrease in intake after adjustment for age, physical activity, smoking, total energy intake, and other lifestyle variables (relative risk (RR), 0.76; 95% confidence interval (CI), 0.69-0.86; P for trend <0.0001). For major weight gain (> or =25 kg), women with the largest increase in intake of fruits and vegetables had a 28% lower risk compared to those in the other extreme group (RR, 0.72; 95% CI, 0.55-0.93; P=0.01). Similar results were observed for changes in intake of fruits and vegetables when analyzed separately. Our findings suggest that increasing intake of fruits and vegetables may reduce long-term risk of obesity and weight gain among middle-aged women.