Human B cells were cultured without added lymphokines, with interleukin 2 (IL2) or interferon-gamma (IFN-gamma) alone, or with a combination of IL2 and IFN-gamma. Treatment with IL2 alone induced differentiation of the B cells, as shown by an increase in the number of immunoglobulin (Ig)-containing cells and plaque-forming cells, and by a larger amount of Ig secreted into the medium. In most of the induced Ig-containing cells, heavy chains but not light chains were detectable by cytoplasmic staining. Treatment with IFN-gamma alone did not stimulate B cell differentiation. However, a combination of IFN-gamma and IL2 was more effective than IL2 alone in inducing B cell differentiation, as measured by further increases in the number of plaque-forming cells and in total Ig secretion. Furthermore, after treatment with both IL2 and IFN-gamma, most cells that contained cytoplasmic heavy chains also contained cytoplasmic light chains. We conclude that IFN-gamma acts in synergy with IL2 in B cell differentiation by enhancing light chain synthesis, leading to secretion of Ig molecules.