Treatment for metastatic melanoma is limited by low response rates to single- or combination-agent chemotherapy. Recent studies have examined the role of biologic modifiers and differentiating agents. This phase II study examined the efficacy and toxicity of combining alpha-2b-interferon (IFN alpha) and 13 cis retinoic acid (cRA) in the treatment of metastatic malignant melanoma. Thirteen patients were treated with IFN alpha (5 x 10(6) units/m2 three times weekly) and cRA (1 mg/kg per day). One patient with lung and adrenal metastases had a partial response 6 months in duration and two patients had stabilization of lung metastases for 2 months. All other patients had progressive disease. Toxicity was substantial with all patients experiencing Eastern Cooperative Oncology Group grade 1-2 fatigue, myalgias, anorexia, stomatitis, and cheilitis. In addition, serum cholesterol and triglycerides were elevated in all patients. Seven patients required 50% dose reductions because of hypertriglyceridemia, fatigue associated with a significant decline in performance status, and severe stomatitis with anorexia and weight loss. One patient discontinued therapy because of a decline in performance status. This study suggests this combination of cRA and IFN alpha is inactive in the treatment of metastatic melanoma and is associated with substantial toxicity.