Multinucleated giant cells are associated with granulomas arising from immunological and nonimmunological inflammatory reactions. They are an integral part of the host immune response to chronic infectious diseases. In the present study we have demonstrated that human lymphocytes when stimulated by specific antigens of T cell mitogens produce a soluble factor that causes peripheral blood monocytes to fuse and form multinucleated giant cells in vitro. Production of the giant cell factor by antigen-stimulated peripheral blood lymphocytes correlates with the existence of cell-mediated immunity to specific antigen. Monocyte-depleted blood lymphocytes, but not purified blood monocytes, produce the giant cell factor when cultured with antigens or T cell mitogens. Gel filtration and physiochemical studies indicate that the lymphocyte-derived giant cell factor is a heat-labile protein of approximately 60,000 mol wt. These findings suggest that multinucleated giant cells in granulomas may be formed by fusion of circulating monocytes in response to the release of a 60,000-mol wt protein from antigen-stimulated T lymphocytes.