Immune‐mediated drug hypersensitivity reactions are an important source of iatrogenic morbidity and mortality. Human leukocyte antigen (HLA)‐B*57:01, HLA‐B*15:02, HLA‐A*31:01, and HLA‐B*58:01 constitute established risk factors and preemptive genotyping of these HLA alleles in patients prior to the initiation of abacavir, carbamazepine, and allopurinol‐based therapies can prevent toxicity and improve patient outcomes. However, the cost‐effectiveness of preemptive HLA testing has only been evaluated in the United States and few countries in Europe and Asia. In this study, we consolidated HLA genotypes from 3.5–6.4 million individuals across up to 74 countries and modeled the country‐specific cost‐effectiveness of genetic testing. We find major ethnogeographic differences in risk allele prevalence, which translated into pronounced differences in the number of patients needed to test to prevent one case of severe hypersensitivity reactions between countries and populations. At incremental cost‐effectiveness ratio thresholds of $40,000, testing of HLA‐B*57:01 in patients initiating abacavir was cost‐effective in the majority of countries with potential exceptions of East Asia, Saudi Arabia, Ghana, and Zimbabwe. For carbamazepine, preemptive genotyping of HLA‐B*15:02 is only cost‐effective across most of East and South Asia, whereas HLA‐A*31:01 testing is likely to be cost‐effective globally. Testing of HLA‐B*58:01 is more likely to be cost‐effective throughout Africa and Asia compared with Europe and the Americas. We anticipate that this data set can serve as an important resource for clinicians and health economists to guide clinical decision making and inform public healthcare strategies.