It is currently thought that T cells with specificity for self-peptide/MHC (pMHC) ligands are deleted during thymic development, thereby preventing autoimmunity. In the case of CD4⁺ T cells, what is unclear is the extent to which self-peptide/MHC class II (pMHCII)-specific T cells are deleted or become Foxp3⁺ regulatory T cells. We addressed this issue by characterizing a natural polyclonal pMHCII-specific CD4⁺ T-cell population in mice that either lacked or expressed the relevant antigen in a ubiquitous pattern. Mice expressing the antigen contained one-third the number of pMHCII-specific T cells as mice lacking the antigen, and the remaining cells exhibited low TCR avidity. In mice lacking the antigen, the pMHCII-specific T-cell population was dominated by phenotypically naive Foxp3⁻ cells, but also contained a subset of Foxp3⁺ regulatory cells. Both Foxp3⁻ and Foxp3⁺ pMHCII-specific T-cell numbers were reduced in mice expressing the antigen, but the Foxp3⁺ subset was more resistant to changes in number and TCR repertoire. Therefore, thymic selection of self-pMHCII–specific CD4⁺ T cells results in incomplete deletion within the normal polyclonal repertoire, especially among regulatory T cells.