The global prevalence of obesity has significantly increased in most industrialized countries. Anti-obesity drugs are scarce, and indications to change their life style are impractical. Therefore, to identify diets able to produce significantly and maintained weight loss is mandatory. The present work evaluated the efficacy of a very low-calorie-ketogenic (VLCK) diet in obesity. A group of obese patients were randomized into two groups: the VLCK diet group and a standard low-calorie diet (LC group). The follow-up period was 12 months. Both groups received external support, counseling, to perform physical activity and adhered to the diet. The VLCK diet induced a 30-45 days of mild ketosis and significant effects on body weight within 15 days. At 2 months, the weight reductions in the VLCK diet and LC diet groups were 13.6 ± 3.9 and 4.8 ± 2.7 kg, respectively (p < 0.0001). At the end of the study, at 12 months, the weight reductions were 19.9 ± 12.3 and 7.0 ± 5.6 kg, respectively (p < 0.0001), and more than 88 % of patients in the VLCK diet group lost more of 10 % of their initial weight. Lean mass was practically unaffected. The VLCK diet was well tolerated and the side effects were moderate and transitory. In a group of obese patients, the VLCK diet was significantly more effective than a standard LC diet. At one year follow-up in the group with VLCK diet, most of the patients loss more than 10 % of their initial weight and lean mass was well preserved.