Allelic variants of FcγR confer distinct phagocytic capacities providing a mechanism for heritable susceptibility to immune complex disease. Human FcγRIIa has two codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The FcγRIIa-H131 is the only human FcγR which recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Therefore, since immune complex clearance is essential in SLE, we hypothesized that FcγRIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis. In a two-stage cross-sectional study, we compared the distribution of FcγRIIA alleles in African Americans with SLE to that in African American non-SLE controls. A pilot study of 43 SLE patients and 39 controls demonstrated a skewed distribution of FcγRIIA alleles, with only 9% of SLE patients homozygous for FcγRIIa-H131 compared with 36% of controls (odds ratio, 0.18; 95% CI, 0.05-0.69, P = 0.009). This was confirmed with a multicenter study of 214 SLE patients and 100 non-SLE controls. The altered distribution of FcγRIIA alleles was most striking in lupus nephritis. Trend analysis of the genotype distribution showed a highly significant decrease in FcγRIIA-H131 as the likelihood for lupus nephritis increased (P = 0.0004) consistent with a protective effect of the FcγRIIA-H131 gene. The skewing in the distribution of FcγRIIA alleles identifies this gene as a risk factor with pathophysiologic importance for the SLE diathesis in African Americans.