Two different allelic polymorphisms among the isoforms of human Fcγ receptors have been defined: the low-responder (LR)-high-responder (HR) polymorphism of huFcγRIIA expressed on both PMN and monocytes and the NA1-NA2 polymorphism of the neutrophil FcγRIII (huFcγRIIIB). To address the issues of whether the LR-HR polymorphism has a significant impact on FcγR-mediated functions in human blood cells and whether any differences in LR-HR might be related to higher FcγR-mediated phagocytosis in NA1 donors, we examined FcγR-specific binding and internalization by donors homozygous for the two huFcγRIIA alleles. PMN from LR homozygotes showed consistently higher levels of internalization of erythrocytes opsonized with pooled human IgG (E-hIgG). The absence of an LR-HR phagocytic difference with erythrocytes opsonized with either anti-FcγRIIA MAb IV.3 or rabbit IgG, as opposed to E-hIgG, suggested that the Fc piece of the opsonin might be important for this LR-HR difference. Accordingly, we studied HR and LR homozygotes with human IgG subclass-specific probes. Both PMN (independent of huFcγRIIIB phenotype) and monocytes from LR donors bound and internalized erythrocytes coated with human IgG2 (E-hIgG2) efficiently, whereas phagocytes from HR donors did so poorly. E-hIgG2 internalization was completely abrogated by blockade of the ligand binding site of huFcγRIIA with IV.3 Fab, indicating that huFcγRIIA is essential for the handling of hIgG2 and that the mechanism of the LR-HR phagocytic difference is at the level of ligand binding to huFcγRIIA. In contrast, the difference in internalization of E-hIgG between NA1 and NA2 homozygous donors was independent of the huFcγRIIA phenotype and did not manifest differences in ligand binding. Thus, the two known allelic polymorphisms of human FcγR have distinct and independent mechanisms for altering receptor function, which may influence host defense and immune complex handling.