Activation of resting T lymphocytes is initiated by the interaction of cell-surface receptors with their corresponding ligands. In addition to activation through the CD3 (T3)-Ti antigen-receptor complex, recent experiments have demonstrated induction of T-cell proliferation through the CD2 (T11) molecule, traditionally known as the erythrocyte(E)-receptor, through which T cells can bind red blood cells (RBC). This 'alternative pathway' of T-cell activation was observed in vitro in response to combinations of anti-CD2 monoclonal antibodies (mAbs) that bind to distinct epitopes of CD2, such as mAbs against T11(2) plus T11(3). The physiological importance of this activation pathway can be assessed only by studying the effects of a naturally occurring ligand of CD2 on T-cell activation. We have recently described such a ligand, a glycoprotein of apparent relative molecular mass 42,000 (Mr 42K) that is expressed on all blood cells and some other tissues. Here we demonstrate that binding of this cell surface molecule, termed T11 target structure or T11TS, to CD2 (T11) induces reactivity in resting T cells to a mitogenic stimulus given by a mAb to the T11(3) determinant or by submitogenic concentrations of anti-T11(2+3) mAbs. Thus, one of the signals required for T-cell activation through the alternative pathway is provided by the interaction of CD2 with a naturally occurring complementary cell-surface molecule.