Malignant melanoma is one of the several human tumors against which interferons have demonstrated significant antitumor activity. Such activity was first observed in early clinical trials with natural human leukocyte interferon; 4 of 75 patients in different institutions achieved partial response to treatment and 5 patients showed minor regression of disease. Subsequently, in a number of trials conducted with recombinant leukocyte interferons, antitumor activity against melanoma was observed consistently. Recombinant interferons have also revealed remarkable activity against malignant melanoma in the human tumor stem-cell assay, with 18 of 60 samples (30%) showing marked inhibition in tumor growth. Recombinant interferons from two different sources were tested in Phase I and Phase II trials against malignant melanoma. In one Phase I trial with interferon alfa-2b, 4 of 23 patients responded to treatment. In another Phase I study using recombinant interferon alfa-2a, 3 of 20 patients achieved objective responses. More recently, a number of Phase II trials were initiated and the detailed results of two Phase II studies have been published. In the first trial using recombinant leukocyte interferon at a dosage times a week, objective regression of tumor was observed in 7 of 31 patients, for a response rate of 22%. Because of severe toxicity associated with this dosage, a second Phase II trial was conducted using a dosage of 12 X 10(6) U/m2 three times a week, and 6 of 30 patients experienced objective regression of disease, for a response rate of 20%. Based on the results of these early trials with recombinant leukocyte interferon, a number of clinical trials using different species of interferon at different doses and treatment schedules were initiated. The preliminary results of these trials are reported here.