The effect of interferon-gamma (IFN-gamma) on antigen-induced and autologous proliferative responses has been investigated. The enhanced proliferative response, which resulted in the presence of IFN-gamma, was found to be the consequence of the increased density of HLA-DR induced on the accessory cells. The enhanced proliferation was at least partly due to a shift in the proliferation time course. The response to tetanus toxoid peaked 1-2 days earlier when IFN-gamma-treated monocytes acted as accessory cells than when untreated monocytes presented the antigen. Modulation of the level of DR by preincubation of the monocytes with anti-DR antibody with and without IFN-gamma demonstrated that both autologous and antigen-driven proliferation was influenced in proportion to the level of DR expressed at the time of stimulation. These experiments point to the importance of IFN-gamma in inducing an accelerated immune response via its effect on the density of DR expression on the accessory cell.