The E receptor is found on virtually all human T cells and is defined by its ability to bind to sheep erythrocytes (SRBCs). It was recently shown that a monoclonal antibody (MoAb) binding to the E receptor regulates interferon-gamma (IFN-gamma) production and lymphocyte activation. Here the effects of SRBCs on IFN production is examined since these bind to the E receptor. IFN-gamma production induced by phytohemagglutinin (PHA) in both fresh peripheral blood mononuclear leukocytes ( PBML ) and T-lymphocyte lines was augmented by 5- to 10-fold when cultured with SRBCs. The SRBCs increased IFN by interacting with the E receptor since its augmenting effect was blocked by the E-receptor MoAb 9.6. The augmenting effect of SRBCs was independent of blastogenic events since DNA synthesis was not similarly augmented by SRBCs and because IFN-gamma production was only increased after blastogenesis had occurred (in already differentiated lymphoblasts or in PBML 2-3 days after induction). Since it was found that only a short pulse of SRBCs was required for their action, this suggests that the studies employing SRBC rosetting as a fractionation technique for investigating the cell source of IFN-gamma should be viewed with caution.