In three consecutive Phase II trials of recombinant interferon alfa-2a (rIFN alfa-2a; Roferon-A Hoffmann-La Roche, Nutley, NJ) involving 96 patients with advanced malignant melanoma, an overall response rate of 22% was observed. For all study participants, the median time to disease progression was 1.7 months, and the median survival was six months. Most regressions occurred within one month of commencing therapy, were usually limited to soft tissue metastases, and were transient. However, responses in three patients were long term, lasting 32+, 36+, and 41+ months. A thrice weekly intramuscular dose of 50 x 10(6) U/m2 produced an intolerable flulike illness concomitant with a median weight loss of 5.6 kg. The addition of cimetidine to the same dose in 35 patients was of no therapeutic value. A dose of 12 x 10(6) U/m2 produced clinically acceptable toxicities, and a median weight loss of 2.1 kg. There was no apparent dose response relationship, nor were there any obvious sequelae from antibody formation to interferon alfa-2a. As single agent therapy in malignant melanoma, interferon alfa-2a was only marginally useful in most patients. Nevertheless, combination regimens of this agent with cytotoxic agents, alternative molecular species of interferon, and lymphokines, notably tumor necrosis factor, offer a conceptually intriguing dimension in the design of future clinical trials.