A repertoire of TCRs is selected in the thymus by interactions with MHC bound to self-derived peptides. Whether self peptides bound to MHC influence the survival of mature T cells in the periphery remains enigmatic. In this study, we show that the number of naive CD4+ T cells that developed in mice with class II MHC bound with endogenous peptides (A b wt) diminished when transferred into mice with A b covalently bound with a single peptide (A b Ep). Moreover, transfer of a mixture of naive CD4+ T cells derived from A b wt and from A b Ep mice into A b Ep mice resulted in the expansion of the latter and decline of the former. In contrast, when wild-type activated CD4+ T cells were transferred into A b Ep or A b wt mice, these cells survived in both recipients for more than 4 wk, but further expanded in the A b wt host. We conclude that to survive, naive CD4+ T cells favor peripheral expression of the class II MHC/peptide complex (es) involved in their thymic selection, whereas some of activated CD4+ T cells may require them only for expansion.