Pancreatic and gastric lipases hydrolyze dietary triglycerides into 2-monoacylglycerols and free fatty acids prior to systemic absorption. Orlistat, a potent gastrointestinal lipase inhibitor, is undergoing review by the Food and Drug Administration as a new treatment for obesity. When given with a fat-containing meal, orlistat 120 mg three times a day reduces fat absorption by approximately 30%, which equates to a decrease in caloric absorption of approximately 200 kcal/d. A 2 year European study found that 75% of obese subjects on low-fat, energy-deficient diets plus orlistat lost and maintained a modest but medically significant amount of weight. The loss was twice as high as that of subjects taking placebo. Side effects in individuals taking the drug, which were related to orlistat's mechanism of action, included oily spotting, flatulence, and frequent loose stools. Patients did not experience frank diarrhea or intestinal malabsorption. Vitamin D and β-carotene levels decreased but remained within the normal range. In summary, orlistat is the first example of a new class of antiobesity drugs that interferes with dietary fat absorption, enhances weight loss and weight maintenance, has tolerable gastrointestinal side effects, and has no major drug toxicity. Orlistat may prove to be useful in clinical practice as an adjunct to nonpharmacological weight management interventions, particularly low-fat energy-deficient diets.