Graves’ Disease (GD, MIM 27500) is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Anti-thyroid drugs (ATDs, including methimazole, carbimazole and propylthiouracil) are relatively simple molecules known as thionamides, which have been cornerstones of GD treatment across the globe. ATDs induced-agranulocytosis, namely thionamide induced agranulocytosis, (TiA, defined as an absolute granulocyte count < 500 per cubic millimeter while taking ATDs), is the most feared adverse effect of ATDs and can occur in 0.1-0.37% of GD patients receiving these medications. Genetic predisposition of TiA was previously unknown. Here we conducted a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves’ disease controls; all ethnic Chinese Han in Taiwan), using two independent methodologies. The first method was direct human leukocyte antigen (HLA) genotyping covering six classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1). The other method was SNP-based genome-wide association study. We demonstrated HLA-B*38:02 (Armitage trend Pcombined = 6.75 × 10-32) and HLA-DRB1*08:03 (Pcombined = 1.83 × 10-9) as independent susceptibility loci. The genome-wide association study identified the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers were 21.48 (95% confidence interval = 11.13-41.48) and 6.13 (95% confidence interval = 3.28-11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increased odds ratio to 48.41 (Pcombined = 3.32 × 10-21, 95% confidence interval = 21.66-108.22). We performed three-dimensional structure modeling to propose possible binding mechanism. These two HLA alleles are not uncommon in Asians but are rare in Caucasians, which implies that there might be additional HLA alleles responsible for TiA in different populations. It is intriguing that both class I and class II HLA loci can contribute to the same idiosyncratic drug adverse effect. Our results could be useful for anti-thyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.