The CD6 scavenger receptor is known to be expressed on virtually all T cells and is supposed to be involved in costimulation, synapse formation, thymic selection and leukocyte migration. Here, we demonstrate that CD6 is differentially expressed by a subpopulation of peripheral CD56^dim natu- ral killer (NK) cells and absent on CD56^bright NK cells. CD56^dimCD16⁺ cells represent the major NK subset in the periphery, and most cells within this group are positive for CD6. Most killer immunoglobulin-like receptor- and immunoglobulin-like transcript-positive cells also belong to the CD6⁺ subpopulation, as expected from their restricted expression on CD56^dim NK cells. In addition, CD6⁺ NK cells are similar to the newly identified CD94^lowCD56^dim NK subpopulation and most distant from the recently defined CD27⁺ NK subpopulation based on the reverse correlation of expression between CD6 and CD27, a marker associated primarily with CD56^bright NK cells. With respect to CD6 function on NK cells, direct CD6 triggering did not result in degranulation but induced secretion of cytokines (interferon-γ and tumor necrosis factor-α) and chemokines [CXCL10 (IP-10), CXCL1 (GRO-α)]. Thus, CD6 expression on peripheral NK cells marks a novel CD56^dim subpopulation associated with distinct patterns of cytokine and chemokine secretion.