Infection with HIV-1 perturbs homeostasis of human T cell subsets, leading to accelerated immunologic deterioration. While studying changes in CD4⁺ memory and naïve T cells during HIV-1 infection, we found that a subset of CD4⁺ effector memory T cells that are CCR7⁻CD45RO⁻CD45RA⁺ (referred to as T_EMRA cells), was significantly increased in some HIV-infected individuals. This T cell subset displayed a differentiated phenotype and skewed Th1-type cytokine production. Despite expressing high levels of CCR5, T_EMRA cells were strikingly resistant to infection with CCR5 (R5)–tropic HIV-1, but remained highly susceptible to CXCR4 (X4)–tropic HIV-1. The resistance of T_EMRA cells to R5-tropic viruses was determined to be post-entry of the virus and prior to early viral reverse transcription, suggesting a block at the uncoating stage. Remarkably, in a subset of the HIV-infected individuals, the relatively high proportion of T_EMRA cells within effector T cells strongly correlated with higher CD4⁺ T cell numbers. These data provide compelling evidence for selection of an HIV-1–resistant CD4⁺ T cell population during the course of HIV-1 infection. Determining the host factors within T_EMRA cells that restrict R5-tropic viruses and endow HIV-1–specific CD4⁺ T cells with this ability may result in novel therapeutic strategies against HIV-1 infection.