Thirty-two melanoma patients treated with lymphoblastoid alpha interferon (Wellferon) were studied for augmentation of five putative parameters of natural immunity including natural killing (NK), antibody-dependent cellular cytotoxicity (ADCC), cell-mediated inhibition of growth in culture of a murine tumor (GIA), and the size of the OKTIO+ and Leu 7+ subpopulations of peripheral blood mononuclear cells (OKTIO and Leu7). This study confirms and extends our previous conclusions that interferon increases GIA and OKTIO. The increases occurred at 24 hr after interferon, both early and late in the course of treatment, and were dose dependent. NK, ADCC, and Leu7 were activated in many patients individually and mean values for NK and Leu7 were increased in the population as a whole. Two patients with complete remission showed dramatically increased natural immunity by the parameters studied, but the pattern of increase was very different for each patient. The current study of lymphoblastoid alpha interferon demonstrates the immunomodulatory potential of interferon given to melanoma patients, but it fails to support the hypothesis that augmentation of these parameters of natural immunity by interferon may result in tumor responses.