FcγRIIIa, considered an intermediate affinity receptor, can variably bind monomeric IgG and appears to have a higher affinity for IgG than the lower affinity FcγRs, FcγRII and FcγRIIIb. We explored this property for both NK cell and monocyte FcγRIIIa and found higher affinity ligand binding by FcγRIIIa expressed on NK cells compared with FcγRIIIa on monocytes. In normal whole blood or plasma (containing 8-11 mg/ml IgG), NK cell FcγRIIIa was fully blocked, but in monocytes FcγRIIIa showed approximately 60% blockade of the binding of mAb 3G8, which binds in or near the ligand binding site. The ligand binding site of NK cell FcγRIIIa was blocked with as little as 2 mg/ml of human IgG, while monocyte FcγRIIIa was only partially (30%) blocked by 2 mg/ml of human IgG. In contrast, plasma containing approximately 26 mg/ml of IgG (obtained from patients receiving therapeutic γ-globulin) showed complete saturation of monocyte FcγRIIIa with blockade of mAb 3G8 binding. These binding differences are not due to allelic polymorphisms or primary sequence differences between donors. Although NK cell and monocyte FcγRIIIa have identical protein cores, they each undergo differential cell type-specific glycosylation. NK cell FcγRIIIa is glycosylated with high mannose- and complex-type oligosaccharides, while monocyte FcγRIIIa has no high mannose-type oligosaccharides. These results indicate that natural glycoforms of FcγRIIIa (cell type-specific glycosylation variants) bind ligand differently, conferring a lower affinity on monocyte/macrophage FcγRIIIa, which makes the receptor ideal for initial immune complex capture and sensitive to moderate changes in serum IgG levels.