Abstract Despite its use widely as a therapeutic agent, and proposed use as vaccine adjuvant, the effect of IFNα on T cell function is poorly understood. As a pleiotropic innate cytokine produced rapidly in response to pathogens, it is well placed to impinge on specific immune responses. The aim of this study was to examine the impact of IFNα on the function of human memory CD4+ T cells using the recall Ags purified protein derivative, tetanus toxoid, and hemagglutinin. IFNα administered either in vivo or added exogenously in vitro tended to enhance proliferative responses of purified protein derivative-specific T cells in marked contrast to the other cognate populations whose responses were often diminished. Purifying the memory CD4+CD45RO+ T cells confirmed IFNα acted directly on these cells and not via an intermediate. The T cells could be divided into two broad categories depending on how IFNα effected their responses to cognate Ag: 1) enhanced proliferation and a striking increase in IFNγ-production compared with smaller increases in IL-10 (increased ratio of IFNγ:IL-10), and 2) neutral or diminished proliferation coupled with a smaller increase in IFNγ relative to the increase in IL-10 (reduced IFNγ:IL-10 ratio). IFNα has a role in modifying memory T cell responses when they are exposed to cognate Ag and may be important in vaccination strategies designed to augment particular Th memory responses.