NK cells can kill antibody-coated target cells following engagement of Fc gamma RIIIA, the major activating Fc gamma R expressed by these cells. The presence of Fc gamma RIIC (CD32C) has also been reported, but its contribution to the Fc gamma R-dependent effector functions of NK cells remains debated. We demonstrate here that inhibitory Fc gamma RIIB is also expressed by a small subset of CD56 super(+)/NKp46 super(+) NK cells and can efficiently down-modulate their Fc gamma R-dependent effector function. Immunofluorescence analyses of NK cells from 52 healthy donors showed the presence of CD56 super(bright)/Fc gamma RII super(-) (5.2% plus or minus 3.4), CD56 super(dim)/Fc gamma RII super(lo/-) (94.1% plus or minus 3.4), and CD56 super(dim)/Fc gamma RII super(bright) (0.64% plus or minus 0.72) cells. QRT-PCR and protein analyses performed on isolated Fc gamma RII super(bright) NK cells indicated that Fc gamma RIIB is strongly expressed by these cells but not by Fc gamma RII super(lo/-) cells. In addition, Fc gamma RII super(bright) cells showed a weaker antibody-dependent degranulation when incubated with IgG-coated target cells compared with Fc gamma RII super(lo/-) NK cells, although a strong Fc gamma RIIIA expression was detected in both cells. Furthermore, the addition of anti-Fc gamma RII Fab paralleled a higher degranulation of Fc gamma RII super(bright) NK cells, indicating a direct role for Fc gamma RIIB in this down-modulating effect. Thus, it is proposed that Fc gamma RIIB super(bright) NK cells represent a new NK cell compartment able to down-modulate NK cell functions triggered by the engagement of activating Fc gamma R.