Recombinant alpha interferons (IFN-alpha) have diverse effects on the immune response. Alpha IFNs have been shown to increase the number of monocyte Fc receptors and Fc dependent phagocytosis in vitro. Therefore, we prospectively evaluated Fc-dependent phagocytic activity in a group of 14 patients with Stage III melanoma receiving from 10 to 100 X 10(6) u of recombinant DNA-produced alpha-2 interferon (IFN-alpha 2) five days a week for four weeks. Monocyte Fc-dependent phagocytosis (FcDP) was assayed by measuring the ingestion of 51Cr-labeled, IgG-coated sheep erythrocytes before, and on Days 2, 5, and 19 of IFN therapy. Each patient was simultaneously compared with the same unmatched normal controls during the assay period. Monocyte FcDP was unchanged in 8/14 patients on each of the three sampling days. Increases in FcDP occurred in 4/14 patients on Day 2 and only 1/14 on Day 19. Recombinant DNA-produced IFN-alpha 2 did not persistently augment monocyte FcDP irrespective of the dose administered. Moreover, there may be untoward effects on monocyte FcDP in vivo from intravenous administration of high dose IFN-alpha 2 since a distinct, but statistically insignificant (p = 0.06) trend of inhibition of FcDP by Day 19 of therapy was observed. Monocyte FcDP activity of normal controls fluctuated from day to day. The intrinsic variability in monocyte FcDP as assessed by this technique may conceal an effect(s) of IFN preparations in vivo. Additional studies are needed to further define the effects of purified IFN preparations on monocyte and tissue-derived macrophage effector functions.