Peripheral T cell maintenance requires a survival signal delivered upon T cell receptor (TCR)-major histocompatibility complex (MHC) molecule interaction. Since self-peptides play a critical role in the intrathymic positive selection of the mature TCR repertoire, we hypothesized an equally important role in T cell persistence. We used mice with a normal expression of MHC class II molecules but a restricted self-peptide complexity (H-2Mα^−/−) to show that an MHC class II-restricted T cell specificity that displays a deficient positive selection in the H-2Mα^−/− thymus shows an impaired persistence after adoptive transfer in H-2Mα^−/− recipients. Finally, a wild-type CD4⁺ TCR repertoire is incompletely maintained in H-2Mα^−/− recipients. These observations suggest that, similar to intrathymic positive selection, the maintenance of the mature TCR repertoire relies on the recognition of self-peptide:self-MHC complexes.