OBJECTIVES: The aim of the present study was to compare the short-term effects of a hypocaloric Mediterranean diet and two high protein diets, with and without whey protein supplementation, on body composition, lipidemic profile, and inflammation and muscle-damage blood indices in overweight, sedentary, young participants. METHODS: Thirty-three young, overweight, male and female participants (mean ± SD age: 22.8 ± 4.8 y; body mass: 85.5 ± 10.2 kg; body fat percentage: 34.3% ± 8.1%) were randomly allocated to three different hypocaloric (-700 kcal/d) diets: a Mediterranean diet (MD; n = 10), a high-protein diet (HP; n = 10) diet, and a high-protein diet with whey supplementation (n = 10). The intervention lasted 6 wk. Body composition and biochemical indices were evaluated 1 wk before and after the nutritional interventions. RESULTS: Body and fat mass were decreased in the MD and HP groups (-3.5% ± 1.1% and -5.9% ± 4.2% for body and fat mass respectively in MD, and -1.7% ± 1.2% and -2.0% ± 1.8% for body and fat mass respectively in HP;P < 0.05), with no significant decline of fat-free mass observed in the MD group. The MD group's diet beneficially altered the lipid profile (P < 0.05), but the HP and HPW groups' diets did not induce significant changes. Subclinical inflammation and muscle-damage indices significantly increased in the HP and HPW groups (7.4% ± 3.5% and 66.6% ± 40.1% for neutrophils and CRP respectively in HP, and 14.3% ± 6.4% and 266.6% ± 55.1% for neutrophils and CRP respectively in HPW; P < 0.05) but decreased in the MD group (1.8% ± 1.2% and -33.3% ± 10.1% for neutrophils and CRP respectivelyc; P < 0.05). Energy intake of carbohydrates and proteins were significantly related to the changes in body composition and biochemical blood markers (r = -0.389 and -0.889; P < 0.05). CONCLUSIONS: Among the three hypocaloric diets, only the Mediterranean diet induced positive changes in body composition and metabolic profile in overweight, sedentary individuals.