Seventeen patients with histologically proven melanoma and measurable metastatic disease received 7-week cycles of fotemustine 100 mg/m2/day on days 1 and 8, and decarbazine (DTIC) 500 mg/m2/day on days 15 and 16, in a prospective open study, to assess the efficacy of fotemustine-DTIC combination. Response rate was 11.7%: one partial response (PR) in brain for 4.5 months, and one PR in brain and lymph nodes for 4 months. There was also one (5.8%) minimal response (MR) in brain, stomach, and lymph nodes for 8 months, and three (17.6%) patients with stable disease. Survival of responders was significantly superior to nonresponders. There was no response in brain without response in extracerebral sites. Toxicity was generally mild and well tolerated by all the patients. Fotemustine-DTIC showed some activity against metastatic melanoma, and should be further evaluated.