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-IFN alpha A 9-36 IU/day i.m. on 5 consecutive days/week. A second group of 11 patients was treated with r-IFN alpha A and oral cimetidine, 1000 mg/day. The third group of 7 patients had i.v. infusions of r-IFN gamma 0.25-0.5 mg/m2 on 3 days/week. Of the 12 r-IFN alpha A-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-IFN alpha A 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 gamma-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-IFN alpha A therapy seems (1) to be of some therapeutic value in the treatment of cutaneous melanoma metastases, (2) to be superior to r-IFN gamma therapy, and (3) that overall response rates improve with the addition of oral cimetidine to r-IFN alpha A treatment.