Sixteen patients with stage IV melanoma, who were heavily pretreated, received 11 mg/m2/day of intravenous Irofulven for five consecutive days every 28 days. There were no objective tumor responses, although one patient exhibited stable disease after 4 cycles. The most common toxicities were grade 1/2 nausea, vomiting, fatigue, anemia, and thrombocytopenia. One patient required a dose reduction for an elevated creatinine while another patient required cessation of treatment because of acute ataxia that may have been related to Irofulven. Based upon these data, Irofulven does not demonstrate significant antitumor activity to warrant further investigation in advanced melanoma.