The combination of dacarbazine (DTIC), cisplatin (DDP), carmustine and tamoxifen (TAM) has been reported to yield a high rate of response in patients with metastatic melanoma, but responders often experience intracranial recurrences. As fotemustine (FOT) has demonstrated activity on cerebral metastases, the rationale of this study was to replace carmustine by FOT in this four-drug regimen. Twenty patients with metastatic melanoma received FOT (100 mg/m2) on days 1 and 8, DTIC (220 mg/m2 per day) and DDP (25 mg/m2 per day) from day 1 to day 3 and from day 28 to day 30, and continuous daily treatment with TAM (20 mg/day). If stabilization or response was observed at the end of the 8th week, patients received maintenance courses of FOT on day 1, and DTIC (220 mg/m2 per day) and DDP (25 mg/m2 per day) on days 1 to 3. Nineteen patients were evaluable. Of these, six had brain metastases. The overall response rate was 10.5% (two out of 19); both of the responders had only partial responsers. The best responding site was lung. No response was obtained in the four patients with evaluable brain metastases, but no patient had therapy failure due to new brain metastases. The median overall survival was 5 months (range 1–45 months). Toxicity was mainly haematological. The use of this combination is not recommended.