Establishment of protective immunity depends critically on IFN-gamma. We show that in human peripheral blood mononuclear cells, low doses of IL-2 greatly potentiate the response of the IFN-gamma gene to mitogen, by over 100-fold. By itself, IL-2 is unable to induce IFN-gamma mRNA to a significant extent. Yet, exposure to IL-2 leads to cellular commitment within a few hours, expressed by greatly enhanced accumulation of IFN-gamma mRNA upon subsequent exposure to phytohemagglutinin. Changes induced by IL-2 do not relieve the requirement for de novo protein synthesis during the early phases of induction of IFN-gamma gene expression. IL-2 may induce a component essential for induction of IFN-gamma mRNA that is utilized during subsequent exposure to a mitogenic signal. Our results demonstrate synergy between IL-2 and mitogen in IFN-gamma gene induction.