Decay-accelerating factor (DAF) is a cell surface protein that protects cells from autologous C-mediated lysis. DAF is one of the first phosphatidylinositol-linked molecules to be described on human T cells. The current studies demonstrate that low levels of DAF are expressed on a majority of freshly isolated human T cells and that DAF expression rapidly increases after T cell activation by mitogens. Moreover, antibodies to DAF induce T cell proliferation when the cells are co-stimulated with phorbol esters. The induction of proliferation is facilitated when the antibodies to DAF cross-linked with a secondary antibody. T cell mitogenesis is largely dependent on the phosphatidylinositol-linked form of DAF, because removal of DAF by a phosphatidylinositol-specific phospholipase C eliminates anti-DAF-induced T cell proliferation. These studies suggest that DAF on the surface of T cells may not only serve to afford protection from autologous C but may also function to transmit signals that induce T cell activation.