A subset of T cells in human peripheral blood expresses CD161 (NKR-P1A) receptors that are primarily associated with NK cells. In the current study we isolated blood T cell subsets according to the expression of CD161 and examined their contents of naive, central memory, and effector memory cells and their capacities for proliferation, cytokine secretion, and natural cytolysis. We found that CD4+ CD161− and CD8+ CD161− subsets contained predominantly naive T cells that secreted high levels of IL-2 after in vitro stimulation, and CD4+ CD161 int and CD8+ CD161 int subsets contained predominantly effector and central memory T cells that secreted high levels of IFN-γ and TNF-α. All of these subsets showed vigorous proliferation after stimulation in vitro, but none had NK lytic activity. Unexpectedly, the CD8+ CD161+ cells contained an anergic CD8α+ CD8β low/− CD161 high T cell subset that failed to proliferate, secrete cytokines, or mediate NK lytic activity.