An open-label, placebo-controlled, randomized, two-way crossover study was performed in 12 healthy volunteers (between 20 and 44 years of age) to assess the effect of orlistat, a gastrointestinal lipase inhibitor that reduces dietary fat absorption and is being developed for weight control in obesity, on the absorption of vitamins A and E. Each participant received a single oral dose of 25,000 IU vitamin A followed 24 hours later by a single oral dose of 400 IU vitamin E on two separate occasions: during oral administration of 120 mg orlistat or placebo three times daily for 9 days. The two treatments were separated by a washout period of at least 2 weeks. Serial blood samples for pharmacokinetic analysis were collected at specified times over 24 hours after each dose of vitamin A for determination of serum concentrations of retinol, and over a period of 5 days after each dose of vitamin E for determination of serum concentrations of alpha-tocopherol, total cholesterol, and triglycerides. Orlistat significantly reduced the absorption of vitamin E (approximately 43% according to maximum concentration and approximately 60% according to area under the concentration-time curve), but not that of vitamin A, at the dose levels studied. The results of this study will aid in the implementation of a vitamin supplementation strategy, should vitamin deficiency occur in patients undergoing orlistat therapy.