Normal subjects received fenretinide (HPR), 200 mg/d, on three schedules. Schedule 1 was treatment for 28 d. Schedule 2 consisted of 14 d of treatment, 3 d hiatus, and a second drug course of 14 d, 10,000 IU vitamin A was administered during the 3-d hiatus. Schedule 3 was 14 d of treatment followed by a rest period of 7 d and then 14 d of treatment. Increase in plasma HPR was accompanied by an even higher increase in the metabolite N-(4-methoxyphenyl)-all-trans-retinamide (MPR). The administration of HPR was associated with a significant reduction in retinol-binding protein (RBP), which returned to pretreatment values after the drug treatment was discontinued. Reduction of plasma retinol was also observed. Use of interrupted schedules with resting periods of 3 and 7 d changed HPR, MPR, and RBP concentrations in plasma. Addition of vitamin A did not affect the pattern of the measured variables in the plasma.