Melanoma patients with multiple brain metastases not amenable to surgery or stereotactic radiotherapy were treated with total brain irradiation in fractions of 2.5 Gy four times weekly, up to 40 Gy. At days 1, 8, and 25100 mg/m2 fotemustine was infused 4 h before irradiation. Of 12 evaluable patients, four showed partial remission and three stabilization in the brain. The median survival in these two groups of patients was 6 months; the survival of the other patients was 2 months. Severe haematological side effects were observed in 6/13 patients. In conclusion, the combination of fotemustine and total brain irradiation seems to be more effective than either treatment alone, but bears the risk of additional bone-marrow toxicity.