Objective. To examine the relationship between allelic polymorphisms of IgG receptors (FcγR) and the development of lupus nephritis in a prospective study, and to determine the distribution of FcγR haplotypes (FcγRIIA and FcγRIIIA genotypes) in lupus patients and disease-free control subjects. Methods. We studied 67 Hispanic systemic lupus erythematosus (SLE) patients from a prospective study of outcome and 53 disease-free control subjects. Patients were followed up longitudinally for 3 years. FcγRIIA and FcγRIIIA genotypes were determined using allele-specific polymerase chain reaction. Results. Nephritis was present in 28% of patients at 11entry into the study and in 69% at the end of 3 years. In the nephritis group (n = 46), as well as the entire SLE cohort, there was a predominance of genotypes with low-binding alleles (FcγRIIa-R131 and FcγRIIIa-F176) at both loci (SLE nephritis patients 89% versus controls 62%; P < 0.002; odds ratio 0.20 [95% confidence interval 0.05-0.6] for risk of nephritis in individuals homozygous for either FcγRIIa-H131 or FcγRIIIa-V176). The frequency of individuals homozygous for high-binding alleles at either locus decreased as the burden of disease increased (P < 0.002, by Mann-Whitney test). There was no linkage disequilibrium between FcγRIIA and FcγRIIIA in Hispanics, yet in the SLE patients, there was a clear overrepresentation of the FcγRIIa-R131;FcγRIIIa-F176 haplotype (SLE patients 48% versus controls 30%) and a decrease in the frequency of the high-binding haplotype (4% versus 23%) (P < 0.002). Conclusion. We observed an increase in the frequency of low-binding FcγR alleles in an SLE population with a high prevalence of renal disease. The apparent selection for the FcγRIIa-R131;FcγRIIIa-F176 haplotype in Hispanic patients suggests that low-binding alleles of both FcγRIIa and FcγRIIIa confer risk for SLE and may act additively in the pathogenesis of disease, whereas the high-binding haplotype FcγRIIa-H131;FcγRIIIa-V176 is protective, particularly in the homozygous state.