Occupancy of the T-cell antigen receptor is insufficient to induce T-cell activation optimally; a second co-stimulatory signal is required. Exposure of T-cell clones to complexes of antigen with major histocompatibility complex molecules in the absence of the co-stimulatory signal induces a state of clonal anergy. This requirement for two stimuli for T-cell activation could have an important role in vivo in establishing peripheral tolerance to antigens not encountered in the thymus. The receptor on T cells required for the co-stimulatory stimulus involved in the prevention of anergy has not been identified. The human T-cell antigen CD28 provides a signal that can synergize with T-cell antigen receptor stimulation in activating T cells to proliferate and secrete lymphokines. Here we report that a monoclonal antibody against the murine homologue of CD28 (ref. 7; J.A.G. et al., manuscript in preparation) can provide a co-stimulatory signal to naive CD4+ T cells and to T-cell clones. Moreover, we demonstrate that this co-stimulatory signal can block the induction of anergy in T-cell clones.