Sixteen patients with metastatic melanoma were treated with N-methylformamide (NMF), a polar-planar compound with in vitro cytotoxic and differentiating properties. Sixteen patients were evaluable for toxicity and 14 for response. The initial four patients received an intravenous bolus of NMF 800 mg/m2 daily for 5 consecutive days every 28 days. Because of excessive gastrointestinal toxicity, the dose was reduced to 700 mg/m2/day for the subsequent 12 patients. Two patients had immediate adverse effects from NMF; one had a grand mal seizure and the other developed severe abdominal pain. Nausea, vomiting and abdominal pain were dose-limiting. Transient elevation of liver function tests occurred in all patients. Myelosuppression was not observed. There were no objective responses among 14 evaluable patients (95% confidence limits 0-20%). One patient with pulmonary metastases had a minor response lasting 13 months. Median time to progression of disease was one month. NMF in these doses and schedule lacks clinical efficacy in the treatment of metastatic melanoma.