Recent studies have shown that interleukin (IL)-4 can affect secretion of immunoglobulins (Igs) or activation of cytotoxic cells by IL-2, while other studies have shown that natural killer (NK) cells/large granular lymphocytes (LGLs) can also affect Ig synthesis. Therefore, we examined the effect of IL-4 with and without IL-2 or human NK/LGLs on pokeweed mitogen (PWM)-stimulated production of IgM and IgG. We found that when IL-4 and/or IL-2 were incubated with peripheral blood lymphocytes and PWM for 7 days and an enzyme-linked immunosorbent assay was run to measure Ig synthesis, IL-4 with IL-2 caused a greater suppression of Ig synthesis than either cytokine alone. A further experiment was done to determine the effect IL-4 and IL-2 would have on LGL suppression of Ig synthesis. IL-4 and IL-2 alone and in combination, when added to LGL, caused the LGL to suppress Ig synthesis to a greater extent than alone. We conclude that IL-4 acts on NK/LGLs separately and jointly with IL-2, to suppress Ig synthesis (IgM and IgG).