IL-2 is a hallmark cytokine secreted by central memory CD4(+) T cells (T(CM)). Although naive cells rapidly secrete IL-2 in response to Ag stimulation, IL-12 inhibits IL-2 secretion in daughter cells as they differentiate into Th1 cells. In this study, we uncover a unique role for IFN-alpha in regulating IL-2 secretion by human T(CM) cells. IFN-alpha synergized with IL-12 to enhance a subset of cells that secreted high and sustained levels of IL-2. These IL-2-secreting cells displayed phenotypic and functional characteristics of T(CM) and were capable of generating IFN-gamma-secreting effectors upon secondary activation. T-bet has been implicated in negatively regulating IL-2 secretion in murine T cells; however, T-bet expression did not inhibit IFN-alpha-dependent IL-2 secretion in human T(CM) cells. Thus, our results highlight a unique role for IFN-alpha in regulating the development of IL-2-secreting human T(CM) cells.