Fifty-one evaluable patients with histologically proven metastatic melanoma and at least one skin metastasis were treated intralesionally with interferon-alpha (IFN-alpha). Twenty-six of the patients were given highly purified natural IFN-alpha 6 Mio. IU three times per week. Twenty-five patients were given 10 Mio. IU three times per week of a recombinant IFN-alpha 2b (rIFN-alpha 2b). All patients were examined for systemic and local responses to this treatment. The systemic responses consisted of nine objective remissions, each of which lasted from 2 to 18 or more months. There were 24 complete or partial local responses. Forty-two of the 51 patients had at least two skin metastases so that IFN-injected and noninjected tumor sites could be compared. The difference between systemic and local efficacy was highly significant statistically (P = 0.0004). The results show that IFN-alpha has clinically observable antitumor activity in malignant melanoma.