We have performed seven phase II trials with recombinant interferons (IFN) involving 191 patients with biopsy-proved, measurable disseminated malignant melanoma. The regimens and numbers of patients have included IFN-alpha 2A, 50 X 10(6) U/m2 subcutaneous (SQ) TIW (regimen A, 31 patients); IFN-alpha 2A, 12 X 10(6) U/m2 SQ TIW (regimen B, 30 patients); IFN-alpha 2A with cimetidine as an immunorestorative agent (regimen C, 35 patients); IFN-gamma (regimen E, 29 patients); IFN-alpha 2A with IFN gamma (Regimen E, 20 patients); IFN-alpha 2A with bis-chloroethylnitrosourea (BCNU) (regimen F, 30 patients); and IFN-alpha 2A with the biochemical modulator, difluoromethylornithine (DFMO) (regimen G, 16 patients). The objective regression rates were as follows: A, 23%; B, 20%; C, 23%; D, 10%; E, 5%; F, 7%; G, 0%. Despite the higher response rate from regimen A, there appeared to be no survival advantage from any of these programs. The median time to progression was 1 month with a median survival time of 6 months. Most regressions involved soft tissue disease, were partial, and occurred within 2-3 months of treatment. Four patients received IFN for approximately 6 months and have manifested extraordinarily durable regressions of greater than 4+ years. The alpha-regimens produced a flu-type illness and anorexia which were dose-related. Leukopenia was most noteworthy with regimens containing gamma-interferon. Ongoing trials involving alternative and improved immune-related modalities are awaited with keen interest.