Background. Rheumatic heart disease (RHD) remains an important cause of morbidity and mortality globally. Several reports have linked the disease to the human leukocyte antigen (HLA) locus but with negligible consistency. Methods. We undertook a genome-wide association study (GWAS) of susceptibility to RHD in 1163 South Asians (672 cases; 491 controls) recruited in India and Fiji. We analysed directly obtained and imputed genotypes, and followed-up associated loci in 1459 Europeans (150 cases; 1309 controls) from the UK Biobank study. For fine-mapping, we used HLA imputation to define classical alleles and amino acid polymorphisms. Results. A single signal situated in the HLA class III region reached genome-wide significance in the South Asians, and replicated in the Europeans (rs201026476; combined odds ratio 1.81, 95% confidence intervals 1.51-2.18, P=3.48x10-10). While the signal fine-mapped to specific amino acid polymorphisms within HLA-DQB1 and HLA-B, with conditioning, the lead class III variant remained associated with susceptibility (P=3.34x10-4), suggesting an independent effect. Conclusions. A complex HLA signal, likely comprising at least two underlying causal variants, strongly associates with susceptibility to RHD in South Asians and Europeans. Crucially, the involvement of the class III region may partly explain the previous inconsistency, while offering important new insight into pathogenesis.