Transcription factor FOXO3a controls The persistence of central memory CD4(+) T cells (T(CM) cells) is a major correlate of immunological protection in HIV/AIDS, as the rate of T(CM) cell decline predicts HIV disease progression. In this study, we show that T(CM) cells and effector memory CD4(+) T cells (T(EM) cells) from HIV(+) elite controller (EC) subjects are less susceptible to Fas-mediated apoptosis and persist longer after multiple rounds of T cell receptor triggering when compared to T(CM) and T(EM) cells from aviremic successfully treated (ST) subjects or from HIV(-) donors. We show that persistence of T(CM) cells from EC subjects is a direct consequence of inactivation of the FOXO3a pathway. Silencing the transcriptionally active form of FOXO3a by small interfering RNA or by introducing a FOXO3a dominant-negative form (FOXO3a Nt) extended the long-term survival of T(CM) cells from ST subjects to a length of time similar to that of T(CM) cells from EC subjects. The crucial role of FOXO3a in the survival of memory cells will help shed light on the underlying immunological mechanisms that control viral replication in EC subjects.