Aim: To assess the efficacy of a specific long-term programme for weight loss maintenance using a new ‘on/ off' Orlistat approach in obese subjects who previously lost more than 10% of their body weight. Methods: 50 patients were followed up during 4 years; 34 completed the study. Subjects were followed up by physicians trained in obesity management. Anthropometrical, biological and psychological parameters were measured. Insulin sensitivity was evaluated by euglycaemic insulin clamp. Orlistat was given in case of weight relapse more than 2.5%. Subjects could take Orlistat on a voluntary basis for special occasions. Results: The BMI of completers remained stable (29.5 ± 0.9 vs. 30.6 ± 1.0 kg/m2). 73% of completers maintained 10% or more of their weight loss. Subjects from the no-regain group improved most of their parameters while the regain group did not. Insulin sensitivity was negatively linked to body weight during the follow up (p < 0.01, r2 = 0.20). A negative relationship has been found between extent of the previous weight loss and the evolution of body weight during the 4 years follow-up (p < 0.01, r2 = 0.26). Orlistat intake showed a body fat lowering effect (p < 0.05). Conclusion: 73% of subjects maintained more than 10% of their weight loss. Subject with a large weight loss amount are at high risk for weight regain. The Orlistat ‘on/off' intake regarding his lowering body fat mass effect seems to be efficient.