AbstractExcessive calorie intake and physical inactivity are considered key determinants of the rapid worldwide increase in obesity prevalence, however the relationship between diet and weight gain is complex. We investigated associations between adherence to a Mediterranean diet and long-term changes in weight and waist circumference in volunteers recruited to the Italian section of the prospective European Prospective Investigation into Cancer and Nutrition (EPIC). We investigated 32,119 cohort members who provided anthropometric measures at recruitment and updated information on recall a mean of 12 years later. Adherence to a Mediterranean diet was assessed using the Italian Mediterranean Index (score range 0–11). Associations between index score and weight and waist changes were assessed by multivariate linear regression models. Risks of developing overweight/obesity and abdominal obesity were investigated by multivariate logistic models. Increasing Italian Mediterranean Index score (indicating better adherence) was associated with lower 5-year weight change in volunteers of normal weight at baseline (β −0.12, 95% CI −0.16 to −0.08 for 1 tertile increase in score), but not in those overweight/obese at baseline (P interaction between Index score and BMI 0.0001). High adherence was also associated with reduced risk of becoming overweight/obese (OR 0.91, 95% CI 0.84–0.99 third vs. first tertile); smaller 5-year change in waist circumference (β −0.09, 95% CI −0.14 to −0.03 for 1 tertile increase in score); and lower risk of abdominal obesity (OR 0.91, 95% CI 0.84–0.99 third vs. first tertile). Adherence to a traditional Italian Mediterranean diet may help prevent weight gain and abdominal obesity.