One hundred forty-five patients with disseminated malignant melanoma have participated in five Phase II clinical trials utilizing leukocyte A recombinant interferon (IFN-alpha 2A) (96 patients), recombinant interferon gamma (rIFN-gamma) (29), or IFN-alpha 2A concomitant with rIFN-gamma (20 patients). The overall response rate was 17%, with most regressions occurring with the IFN-alpha 2A regimens. The median times to progression (1 month) and survival (6 months) were generally similar to those from chemotherapeutic agents. However, a limited cohort of patients had complete regressions or durable partial responses even after treatment was discontinued or maintained at less than or equal to 25% of the starting dosage. Most objective regressions were partial, occurred in nonvisceral sites, and were detected within 2 months of the beginning of therapy. The most noteworthy sequelae from these regimens were predominantly constitutional, but without any obvious long-term complications. These interferon programs can be conveniently self-administered on an outpatient basis. Although single-agent interferon regimens for advanced malignant melanoma will probably not offer a substantive therapeutic advance, combinations of these molecules with other biological agents (tumor necrosis factor), biochemical modulators (difluoromethylornithine), and cytotoxic agents (bischloroethylnitrosourea, BCNU) offer innovative therapeutic dimensions in the design of future clinical investigations.