Vitamin A and its derivatives, the retinoids, have antiproliferative effects and may induce cellular differentiation. Etretinate, a synthetic retinoid, has a more favorable therapeutic index experimentally than all-trans-retinoic acid or 13-cis-retinoic acid. Ninety patients with superficial papillary bladder tumors stages Ta and T1 entered a prospective randomized double-blind multicenter trial in Switzerland. Seventy-nine of the patients were eligible and received either 25 mg of etretinate or a placebo orally each day. The early withdrawal of a significantly greater number of patients in the placebo group for treatment failure during the first year of the study resulted in a secondary positive selection in this group. High-risk patients were removed and low-risk patients remained. In those patients who had tumor recurrences after randomization, the time to first recurrence was similar in both groups with 13.5 and 13.6 months in the placebo and etretinate groups, respectively. However, the mean interval to subsequent tumor recurrence was significantly longer in the etretinate group. The mean interval between recurrences in these subgroups was 12.7 months in the placebo arm and 20.3 months in the etretinate arm (p = 0.006). Consequently, the number of transurethral resections per patient-year was also reduced significantly in the etretinate group (p < 0.001). In patients with more than one transurethral resection of papillary tumors before randomization, the annual transurethral resection rate in the two treatment groups dropped from 1.7 to 1.3 in the 30 patients in the placebo group (NS, p = 0.1) and from 2.1 to 0.95 in the 25 patients in the etretinate group (p < 0.001). The side effects of etretinate (cheilitis, dryness of mucous membranes and skin) were acceptable to most patients. The relationship of the 3 myocardial infarcts observed in the etretinate group to the retinoid is not clear. Despite their significant effect on the recurrence rate of superficial papillary bladder tumors, retinoids should only be used in well-controlled prospective trials until more is known about their dosage-toxicity profiles.