Interleukin-4 induced the formation of foreign body-type giant multinucleated cells from human monocyte-derived macrophages, an effect that was optimized with either granulocyte-macrophage colony-stimulating factor or interleukin-3, dependent on the concentration of interleukin-4, and specifically prevented by anti-interleukin-4. Very large foreign body giant cells and, predominantly, giant cell syncytia with randomly arranged nuclei and extensive cytoplasmic spreading (285 +/- 121 nuclei and 1.151 +/- 0.303 mm2 per syncytium) were consistently obtained. Under otherwise identical culture conditions, relatively much smaller Langhans-type giant cells with circularly arranged nuclei were induced with a previously described combination of interferon-gamma plus granulocyte-macrophage colony-stimulating factor or interleukin-3 (16 +/- 6 nuclei and 0.033 +/- 0.013 mm2 per giant cell); their formation was prevented by anti-interferon-gamma but not by anti-interleukin-4. Similar rates of macrophage fusion were obtained in both culture systems (72 +/- 5% and 74 +/- 6%, respectively), but these two morphological variants did not occur simultaneously or form from one another within the 10-day culture period. These findings demonstrate that interleukin-4 is a potent human macrophage fusion factor and that differential regulation of macrophage fusion by interleukin-4 and interferon-gamma may lead to morphological variants of multinucleated giant cells.