Natural killer (NK) cells are critical for the first-line defense in infection. Treated viremic HIV-1 infection is associated with the expansion of an anergic subset of CD3−CD56−CD16+ NK cells unable to respond to stimulation with MHC-devoid target cells or with mitogens. These CD3−CD56−CD16+ NK cells expressed SHIP-1 and had significantly reduced perforin levels. This observation suggests a mechanism for the reduced functional activity of CD3−CD56−CD16+ NK cells in chronic HIV-1 infection.