As a model system to explore the functional consequences of structural variants of human Fcγ receptors (FcγR), we have investigated FcγR-mediated phagocytosis in relation to the NA1-NA2 polymorphism of FcγRIII (CD16) on neutrophils (FcγRIIIPMN). The neutrophil-specific NA antigen system is a biallelic polymorphism with codominant expression demonstrating a gene dose effect with the anti-NA1 MAb CLB-gran 11 in a large donor population. To explore the impact of this allelic variation of FcγRIIIPMN on phagocytosis, we used two FcγRIII-dependent probes, IgG-sensitized erythrocytes (EA) and concanavalin A-treated erythrocytes (E-ConA). Comparison of FcγR-mediated phagocytosis by PMN from NA1 subjects and from NA2 subjects showed lower levels of phagocytosis of both probes by the NA2 individuals. The difference was most pronounced with lightly opsonized EA: at the lowest level of sensitization the phagocytic index was 72% lower for NA2 donors, whereas at the highest level of sensitization it was 21% lower (P < 0.003). Blockade of FcγRII with MAb IV.3 Fab amplified by threefold the difference between NA1 and NA2 donors. NA1 and NA2 individuals had identical phagocytic capacities for the non-FcγRIII probes, serum-treated and heat-treated zymosan. These individuals did not show differential quantitative cell surface expression of FcγRIIIPMN measured by a panel of anti-CD16 MAb (3G8, CLB FcR-gran 1, VEP13, BW209/2) and by Scatchard analysis of 125I-IgG dimer binding. The difference in FcγR-mediated phagocytosis was not explicable on the basis of differential collaboration of FcγRIIIPMN alleles with FcγRII, since (a) the difference in phagocytic capacity between NA1 and NA2 individuals was readily apparent with the E-ConA probe (which is independent of FcγRII) and (6) the difference in phagocytosis of EA was magnified by KcγRII blockade. The demonstration that allelic polymorphisms in FcγR can have significant consequences for physiological functions implies that within the structural complexity of human FcγRs, including both allelic forms and cell type-specific isoforms, there will be differences in quantitative, and perhaps qualitative, function with potential importance for disease processes.