Importance Carriage of HLA-B*58:01 has been shown to be associated with allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) in many populations globally; however, there is a critical need to investigate whether this is generalizable to populations of mixed ancestry, such as those in the US. Objective To assess the association of human leukocyte antigen (HLA) class I and II in a cohort of US patients who received a diagnosis of allopurinol-induced SJS/TEN or DRESS compared with allopurinol-tolerant and population control participants. Design, Setting, and Participants This genetic association study included consenting individuals who had specialist-adjudicated allopurinol-induced SJS/TEN or DRESS (collectively allopurinol-induced severe cutaneous adverse reactions [SCARs]) between January 1, 2015, and December 31, 2024. HLA carriage in these individuals was compared with allopurinol-tolerant and population control participants identified through the Vanderbilt University Medical Center biobank, which includes 94 489 individuals with imputed HLA class I and II typing from genotyping array data. Data were analyzed from January 2025 to August 2025. Main Outcomes and Measures The main outcome measure was the association of HLA class I and II alleles with allopurinol-induced SCARs. HLA class I and II conditional logistic regression case-control analyses were performed between patients with allopurinol-induced SCARs and both population control and allopurinol-tolerant control participants matched on age, sex, and self-identified race. Odds ratios (ORs) and 95% CIs were reported, with Bonferroni-corrected P &lt; .05. Results This genetic association study used conditional logistic regression analyses and included 16 patients with allopurinol-induced SCAR (mean [SD] age, 61.1 [12.6] years; 9 female patients [56.25%] and 7 male patients [43.75%]) and 160 allopurinol-tolerant control participants matched 10:1. Two HLA class I alleles were found to be independently associated with increased risk of allopurinol-induced SCAR: HLA-B*58:01 (OR, 28.0 [95% CI, 8.6-100.6]) and HLA-A*34:02 (OR, 20.6 [95% CI, 3.3-131.1]). No HLA class II alleles meeting the Bonferroni-corrected P &lt; .05 level of significance were identified. Conclusions and Relevance These findings suggest that although HLA-B*58:01 was found to be associated with allopurinol-induced SCARs, generalizing findings from previous studies, the allele was absent in more than one-third of the patient cohort and is therefore an incomplete indicator of risk. Importantly, in the US allopurinol-induced SCAR cohort, HLA-A*34:02 was found to be a second independent genetic risk factor for allopurinol-induced SCARs. These findings underscore the need to conduct population-based studies that both reproduce known and uncover novel HLA associations to reduce harm through contributions to screening, risk stratification, and diagnosis.