T cell activation, a critical event in adaptive immune responses, depends on productive interactions between T cell receptors (TCRs) and antigens presented as peptide-bound major histocompatibility complexes (pMHCs). Activated T cells lyseinfected cells, secrete cytokines, and perform other effector functions with various efficiencies, which depend on the binding parameters of the TCR-pMHC complex. The mechanism through which binding parameters are translated to the efficiency of T cell activation, however, remains controversial. The "affinity model" suggests that the dissociation constant (K(D)) of the TCR-pMHC complex determines the response, whereas the "productive hit rate model" suggests that the off-rate (k(off)) is critical. Here, we used mathematical modeling to show that antigen potency, as determined by the EC(50) (half-maximal effective concentration), which is used to support K(D)-based models, could not discriminate between the affinity and the productive hit rate models. Both models predicted a correlation between EC(50) and K(D), but only the productive hit rate model predicted a correlation between maximal efficacy (E(max)), the maximal T cell response induced by pMHC, and k(off). We confirmed the predictions made by the productive hit rate model in experiments with cytotoxic T cell clones and a panel of pMHC variants. Thus, we propose that the activity of an antigen is determined by both its potency (EC(50)) and maximal efficacy (E(max)).