We report the effects of a Mediterranean-style diet, with or without calorie restriction, on biomarkers of aging and oxidative stress in overweight men. 192 men were randomly assigned to either a Mediterranean-style diet or a conventional diet. The intervention program was based on implementation of a Mediterranean dietary pattern in the overweight group (MED diet group), associated with calorie restriction and increased physical activity in the obese group (lifestyle group). Both groups were compared with participants in two matched control groups (advice groups). After 2 years, there was a significant difference in weight loss between groups, which was -14 kg (95% CI -20 to -8) in lifestyle groups and -2.0 kg (-4.4 to 0) in the advice groups, with a difference of -11.9 kg (CI -19 to -4.7 kg, P < .001); moreover, there was a significant difference between groups at 2 years for insulin (P = .04), 8-iso-PGF2α (P = .037), glucose (P = .04), and adiponectin (P = .01). Prolonged adherence to a Mediterranean-style diet, with or without caloric restriction, in overweight or obese men is associated with significant amelioration of multiple risk factors, including a better cardiovascular risk profile, reduced oxidative stress, and improved insulin sensitivity.