Evidence from population genetics, gene expression microarrays, and assays of ex vivo T-cell function indicates that the cytotoxic T lymphocyte (CTL) response to human T-lymphotropic virus type 1 (HTLV-1) controls the level of HTLV-1 expression and the proviral load. The rate at which CTLs kill autologous HTLV-1-infected lymphocytes differs significantly among infected people, but the reasons for such variation are unknown. Here, we demonstrate a strong negative cor-relation between the frequency of CD4(+)FoxP3(+) Tax(-) regulatory T cells (T(regs)) in the circulation and the rate of CTL-mediated lysis of autologous HTLV-1-infected cells ex vivo. We propose that the frequency of CD4(+)FoxP3(+) Tax(-) T(regs) is one of the chief determinants of the efficiency of T cell-mediated immune control of HTLV-1.