OBJECTIVE Obesity is a well-known risk factor of atherosclerosis. Recent studies showed that obesity is associated with enhanced lipid peroxidation. The aim of this study is to investigate the effect of weight reduction with orlistat treatment on lipid peroxidation levels. We assessed lipid peroxidation by measuring the concentration of plasma malondialdehyde (MDA). METHODS A randomized, controlled, open-label 6-month study. METHODS In total, 36 obese (body mass index (BMI) >30 kg/m2) and 11 healthy age-matched control subjects were enrolled in the study. METHODS Fasting glucose, triglyceride, total cholesterol, HDL cholesterol and LDL cholesterol and MDA levels were measured in both groups. Obese subjects received orlistat, 120 mg three times daily together with hypocaloric diet. After 6 months of treatment laboratory tests were repeated. RESULTS MDA levels were significantly higher in obese patients than the control group (P<0.0001). After 6 months of treatment in obese subjects, the mean weight of the patients decreased by 6.8 kg, the BMI by 3.2 kg/m2. Plasma MDA levels were significantly reduced by weight loss from 2+/-0.77 to 0.89+/-0.41 nmol/ml (P<0.001). BMI correlated with MDA levels at baseline (r=0.6, P<0.0001). Changes in BMI was positively associated with plasma MDA level reduction (r=0.36, P<0.05). CONCLUSIONS These results indicate that obesity is associated with increases in endogenous lipid peroxides. Our data show that the indicator of lipid peroxidation-MDA-falls markedly in association with weight loss with orlistat. The demonstration of decreased free radical generation has important implications for oxidative mechanism underlying obesity-associated disorders.