In the course of viral infection, the immune system exploits only a fraction of the available CTL repertoire and focuses on a few of a myriad of potentially antigenic peptides. This phenomenon, known as immunodominance, depends on a number of factors, including antigen processing and transport, MHC binding, competition for antigen-presenting cells, availability of the CD8 T cell repertoire and other mechanisms that function largely by restricting the immune response. Here we elucidate a novel mechanism that increases the immunodominance of the epitope rather by enhancing the immune response. Using a peptide-specific MHC-restricted mAb and functional assays of CTL activation, we show that T cells with high avidity for the immunodominant, H-2D(d) restricted, P18-I10 epitope expand rapidly following immunization, and this expansion in turn determines the level of the P18-I10 epitope immunodominance. This proliferation has little dependence on the number of MHC-peptide complexes. Since most self-reactive T cells of high avidity are depleted in the thymus, the selection of immunodominant epitopes based on the expansion of high-avidity T cells in the periphery reduces the potential for autoimmunity.