Twenty-five patients with metastatic malignant melanoma were treated with isotretinoin (13-cis-retinoic acid) orally at 1 mg/kg daily and recombinant interferon alfa-2a (IFN-α) subcutaneously at 3 million units daily for 16–48 weeks. Therapy was well tolerated; fatigue and hyperlipidemia were the most frequent dose-limiting toxicity and necessitated dose reductions in 14 patients. Two patients achieved a complete response, and 3 responded partially for a total response rate of 20% (95% confidence interval: 4–36%). Responses occurred primarily in patients with limited tumor burden and disease confined to the skin and lymph nodes. Significant elevations in peripheral blood 2′-5′-oligoadenylate synthetase activity and natural killer activity were observed with therapy. The magnitude of these changes, however, was not predictive of response. Biopsy specimens of two responding lesions showed extensive necrosis of tumor. One specimen showed large aggregates of melanophages in association with tumor. The combination of isotretinoin and IFN-αis an active, easily administered regimen with acceptable toxicity for metastatic malignant melanoma