Objective. Although low-affinity alleles of human Fcγ receptor types IIA and IIIA (FcγRIIA and FcγRIIIA, respectively) polymorphisms have been associated with systemic lupus erythematosus (SLE) in case-control studies, the relative contribution of these genes to SLE susceptibility has not been resolved. Methods. We analyzed the distribution of alleles of FcγRIIA, FcγRIIIA, and FcγRIIIB in 126 multiplex SLE pedigrees and FcγRIIA and FcγRIIIA in a case-control replication study, using allele-specific polymerase chain reaction and direct sequencing of genomic DNA. Statistical tests of association were performed to detect evidence of linkage between the single nucleotide polymorphisms and SLE. Results. We found evidence for linkage at both the FcγRIIIA (single-point nonparametric linkage [NPL] 1.8, P = 0.038; multipoint NPL 2.7, P = 0.004) and the FcγRIIA (single-point NPL 2.0, P = 0.021; multipoint NPL 2.6, P = 0.006) loci, but not the FcγRIIIB locus. Family-based tests of association demonstrated increased transmission of the low-affinity F176 allele at the FcγRIIIA locus (odds ratio [OR] 2.18, P = 0.0005 by transmission disequilibrium test and P = 0.002, by pedigree disequilibrium test [PDT]), but little evidence of preferential transmission of alleles at FcγRIIA (P = 0.089 by PDT). Stratification by ethnicity showed preferential transmission of the associated FcγRIIIA allele both in families of African American ancestry and in those of European American ancestry. Despite significant linkage disequilibrium between these genes, 2- and 3-locus haplotype analysis of the extended Fcγ receptor cluster did not reveal any significant association beyond that observed with FcγRIIIA alone. In a large case-control replication study of 438 patients with SLE and 219 controls, FcγRIIIA provided the strongest evidence of an FcγR-SLE association (additive model: V/V 176 versus V/F 176 OR 1.51, V/V 176 versus F/F 176 OR 1.98, P = 0.007). Conclusion. To our knowledge, these data are the first to demonstrate linkage and both family-based and case-control-based association of FcγRIIIA with SLE. These data provide genetic evidence supporting a role for the physiologically relevant single nucleotide polymorphism of the FcγRIIIA gene in the pathophysiology of this complex genetic disease.