Red blood cell (RBC) transfusion remains a critical therapeutic intervention in sickle cell disease (SCD); however, the apparent propensity of some patients to regularly develop RBC alloantibodies after transfusion presents a significant challenge to finding compatible blood for so-called alloimmunization responders. Predisposing genetic loci have long been thought to contribute to the responder phenomenon, but to date, no definitive loci have been identified. We undertook a genome-wide association study of alloimmunization responder status in 267 SCD multiple transfusion recipients, using genetic estimates of ancestral admixture to bolster our findings. Analyses revealed single nucleotide polymorphisms (SNPs) on chromosomes 2 and 5 approaching genome-wide significance (minimum P = 2.0 × 10-8 and 8.4 × 10-8, respectively), with local ancestry analysis demonstrating similar levels of admixture in responders and nonresponders at implicated loci. Association at chromosome 5 was nominally replicated in an independent cohort of 130 SCD transfusion recipients, with meta-analysis surpassing genome-wide significance (rs75853687, P meta = 6.6 × 10-9), and this extended to individuals forming multiple (>3) alloantibodies (P meta = 9.4 × 10-5). The associated variant is rare outside of African populations, and orthogonal genome-wide haplotype analyses, contingent on local ancestry, revealed genome-wide significant sharing of a ∼60-kb haplotype of African ancestry at the chromosome 5 locus (Bayes Factor = 4.95). This locus overlaps a putative cis-acting enhancer predicted to regulate transcription of ADRA1B and the lncRNA LINC01847, both members of larger ontologies associated with immune regulation. Our findings provide potential insights to the pathophysiology underlying the development of alloantibodies and implicate non-RBC ancestry-limited loci in the susceptibility to alloimmunization.