Antiretroviral therapy (ART) induces rapid suppression of viral replication and a progressive replenishment of CD4+ T cells in HIV-infected individuals. However, the effect of ART on restoring pre-existing memory CD4+ T cells specific for common copathogens is still unclear. To better understand the dynamics of Ag-specific CD4+ T cells during ART, we assessed the frequency, functional capacity, and memory profile of CD4+ T cells specific for Mycobacterium tuberculosis and CMV in 15 HIV-infected individuals before and 1 y after ART initiation. After ART initiation, the frequency of M. tuberculosis–specific CD4+ T cells showed little change, whereas CMV-specific CD4+ T cells were significantly lower (p= 0.003). There was no difference in the polyfunctional or memory profile of Ag-specific CD4+ T cells before and after ART. The replenishment of Ag-specific CD4+ T cells correlated with the memory differentiation profile of these cells prior to ART. Pathogen-specific CD4+ T cells exhibiting a late differentiated profile (CD45RO+ CD27−) had a lower capacity to replenish (p= 0.019; r=− 0.5) compared with cells with an early differentiated profile (CD45RO+ CD27+; p= 0.04; r= 0.45). In conclusion, restoration of copathogen-specific memory CD4+ T cells during treated HIV infection is related to their memory phenotype, in which early differentiated cells (such as most M. tuberculosis–specific cells) have a higher replenishment capacity compared with late differentiated cells (such as most CMV-specific cells). These data identify an important, hitherto unrecognized, factor that may limit restoration of copathogen immunity in HIV-infected individuals on ART.