To assess the long-term benefits of orlistat treatment [ORL], 743 adult male and female obese patients (body mass index 28–40 kg/m 2) were recruited to a 4-week single blind, placebo [PLA] run-in period on a mildly hypocaloric diet (600 kcal/d deficit) and 688 were then randomised to receive either ORL 120 mg tid (n=345) or PLA (n=343) for 52 weeks. After 52 weeks, the diet was adjusted to compensate for lost weight and patients within each group randomly sub-divided to continue on the same treatment [ORL/ORL or PLA/PLA] or to switch to the alternative treatment [ORL/PLA or PLA/ORL]. Throughout the study weight, serum lipids, fasting glucose and blood pressure were measured regularly. At 52 weeks, the mean weight loss in the ORL group was 10.25% (vs PLA 6.16%; p=0.000) and at 104 weeks the mean weight loss in the ORL/ORL group was 8.07% (vs PLA/PLA 4.49%; p=0.000). Patients who switched from ORL to PLA at 52 weeks regained 52% of their lost weight, with a mean total loss of 5.97% at 104 weeks. Patients with LDL-cholesterol>3.362 mmol/L at baseline showed a decrease of −5.5% in the ORL group (vs +2.25% in the PLA group) after 52 weeks and −7.5% in the ORL/ORL group (vs +4.9% in the PLA/PLA group) after 104 weeks. Diastolic blood pressure (DBP) was reduced after 52 weeks of treatment with ORL (−8.2 mmHg) and with PLA (−6.1 mmHg) in patients with DBP>90 mmHg. After 104 weeks, the overall changes in DBP were −7.9 mmHg vs +3.6 mmHg for ORL/ORL and PLA/PLA patients, respectively. The study showed that, combined with diet, treatment with orlistat produces significant and clinically relevant reductions in weight and that the associated benefits in improved risk factors are maintained throughout 2 years of treatment.