Introduction: Rheumatic heart disease (RHD), a sequela of rheumatic fever characterized by permanent heart valve damage, is the leading cause of cardiac surgery in Africa. However, its pathophysiologic characteristics and genetics are poorly understood. Understanding genetic susceptibility may aid in prevention, control, and interventions to eliminate RHD. Objective: To identify common genetic loci associated with RHD susceptibility in Black African individuals. Materials and Methods: 4809 genome-wide association study (GWAS) participants and 116 independent trio families were enrolled from 8 African countries. Clinical and echocardiography screening were performed on all GWAS participants and trio probands. Results: This study included 4809 African participants (2548 RHD cases and 2261 controls; 3301 women [69%]; mean [SD] age, 36.5 [16.3] years). The GWAS identified a single RHD risk locus, 11q24.1 (rs1219406 [odds ratio, 1.65; 95%CI, 1.48-1.82; P=4.36x10−8]), which reached genome-wide significance in Black Africans. The study also replicated a previously reported association in Pacific Islanders (rs11846409) at the immunoglobulin heavy chain locus, in the meta-analysis of Black and admixed Africans (odds ratio, 1.16; 95%CI, 1.06-1.27; P=1.19x10−3). In support of the known polygenic architecture for RHD, over-transmission of a polygenic risk score from unaffected parents to affected probands was observed (polygenic transmission disequilibrium testing mean [SE], 0.27 [0.16] SDs; P=0.04996), and the chip-based heritability was estimated to be high at 0.49 (SE = 0.12; P=3.28x10−5) in Black Africans. Conclusion and Significance/Implication: This study revealed a novel candidate susceptibility locus exclusive to Black African individuals and an important heritable component to RHD susceptibility in African individuals.