Fc receptor-like proteins (FcRLs) are a growing family of molecules homologous to FcγRI. Whereas all 7 previously reported Fc receptor homologs are expressed by B cells, here we report a new receptor, FcRL6, that is expressed by cytolytic cells including natural killer (NK) cells and effector and effect or-memory CD8+ T cells. FcRL6 contains a novel cytoplasmic cysteine-rich motif and recruits SHP-2 through a phosphorylated ITIM, indicating a potential signaling function in effector lymphocytes. In vitro, FcRL6 does not greatly influence NK-cell or CD8+ T-cell-mediated cytotoxicity and has minimal impact on cytokine secretion. However, FcRL6 expression among T lymphocytes is greatly expanded in human immunodeficiency virus type 1 (HIV-1)-infected individuals, and includes not only effector and effector-memory CD8+ T cells but also populations of CD4+ T cells. Expansion of FcRL6-positive lymphocytes is not related to viral load, but is indicative of the dysregulated expansion of terminally differentiated effector lymphocyte populations in response to chronic HIV-1 infection and may serve as an important marker for chronic immune activation and for tracking the generation of effector cells following immune stimulation. © 2007 by The American Society of Hematology.