CD4(+) T cells are activated upon recognition of peptide antigen in the context of MHC class II molecules, expressed by specialized APC. In this study, we show that CD4(+) T cells cross-compete for antigenic complexes on the surface of APC, inhibiting activation of other potentially reactive T cells of the same and differing specificities. T cells with either a higher affinity receptor for antigen or which have undergone prior activation compete more efficiently than low affinity or resting T cells. This implies that T-cell avidity for the APC is primarily responsible for the competitive advantage. We also provide evidence that the mechanism for competition is steric hindrance of the surface of the APC, rather than T-cell-mediated sequestration or internalization of antigenic complexes. This is because removal of competing T cells restores the antigenic potential of the APC, and APC fixation does not abrogate competition. Demonstration that competition for access to APC can also occur in vivo suggests that this process may represent a physiologically important mechanism for influencing the quality and quantity of CD4(+) T-cell responses.