Forty-four hyperlipidemic obese subjects, selected because of their refractoriness towards diet-therapy, participated voluntarily in a 12-week double-blind study comparing the effects of a long-acting fenfluramine (Ponderal Pacaps) to those of a placebo. In spite of no dietetic intervention, a significant 3-kg weight loss (P less than 0.001) was observed in the fenfluramine-treated group, accompanied by a significant improvement of most atherogenic parameters of plasma lipoproteins. Fenfluramine-induced weight loss produced decrease in total cholesterol (P less than 0.05), total triglycerides (P less than 0.05), LDL cholesterol (P less than 0.05), total apoprotein B (P less than 0.005) and LDL apoprotein B (P less than 0.001). An apoprotein B LDL depletion seemed to occur, as suggested by the reduction of LDL cholesterol/apoprotein B ratio (P less than 0.001). Total plasma apoprotein A did not change but the total apoprotein B/total apoprotein A ratio decreased significantly (P less than 0.005). Moreover, fenfluramine increased both HDL phospholipid (P less than 0.005) and HDL cholesterol (P less than 0.05) resulting in a fall of the atherogenic LDL-cholesterol/HDL cholesterol ratio (P less than 0.001) as well as an elevation of the anti-atherogenic HDL cholesterol/LDL + VLDL cholesterol ratio (P less than 0.001). The placebo group demonstrated some improvement in lipid blood parameters without weight loss, indicating a possible qualitative amelioration of nutritional habits. Thus, fenfluramine reduces the risk for cardiovascular disease in hyperlipidemic obese individuals not responding to behavioral intervention.