A total of 30 patients with progressively growing visceral and/or cutaneous malignant melanoma metastases were entered in a prospective phase II trial comparing three different therapeutic regimens of recombinant interferons (r-IFN). The first group of 12 patients received r-IFNA 9–36 IU/day i.m. on 5 consecutive days/week. A second group of 11 patients was treated with r-IFNA and oral cimetidine, 1000 mg/day. The third group of 7 patients had i.v. infusions of r-IFN 0.25–0.5 mg/m² on 3 days/week. of the 12 r-IFNA-treated patients, 1 responded (complete response, CR), 5 patients exhibited no change (NC), 3 patients had progressive disease (PD), and 3 patients could not be evaluated after therapy. In the group treated with r-IFNA plus cimetidine 3 patients responded (1 CR, 2 partial responses) and 3 exhibited NC. The remaining patients showed PD. Treatment responses were found exclusively in patients with cutaneous and/or lymph node metastases. In contrast, none of the r-IFN-treated patients responded to therapy. Known IFN side effects of varying degrees, sometimes severe, were observed in all patients. Despite the small numbers of patients treated, our preliminary data indicate that r-IFNA therapy seems (1) to be of some therapeutic value in the treatment of cutaneous melanoma metastases, (2) to be superior to r-IFN therapy, and (3) that overall response rates improve with the addition of oral cimetidine to r-IFNA treatment.