To investigate safety, compliance, and efficacy, on weight loss and cardiovascular risk factors of a multiphasic dietary intervention based on meal replacements, including a period of very low calorie diet (VLCD) in a population of obese patients. Anthropometric parameters, blood tests (including insulin), dual-energy-X-ray absorptiometry (DXA), and questionnaires for the assessment of safety and compliance before and after (phase I) a 30-day VLCD, 700 kcal/day, normoproteic, 50 g/day carbohydrate, four meal replacements; (phase II) a 30-day low calorie diet (LCD), 820 kcal/day, three meal replacements plus a protein plate; (phase III) 60-day LCD, 1,100 kcal/day, two meal replacements plus two protein plates and reintroduction of small amounts of carbohydrates; (phase IV) 60-day hypocaloric balanced diet (HBD), 1,200 kcal/day, one meal replacement, two protein plates and the reintroduction of carbohydrates. 24 patients (17 females, 7 males, mean BMI 33.8±3.2 kg/m2, mean age 35.1±10.2 years) completed the study. The average weight loss was 15.4±6.7%, with a significant reduction of fat mass (from 32.8±4.7 to 26.1±6.3% p<0.05) and a relative increase of lean mass (from 61.9±4.8 to 67.1±5.9% p<0.05). An improvement of metabolic parameters and no variations of the liver and kidney functions were found. A high safety profile and an excellent dietary compliance were seen. The VLCD dietary program and the replacement dietary system described here is an effective, safe, and well-tolerated treatment for weight control.