The MR1 antigen-presenting system is conserved among mammals and enables T cells to recognize small molecules produced by bacterial pathogens, including Mycobacterium tuberculosis (M. tb). However, it is not known whether MR1-mediated antigen presentation is important for protective immunity against mycobacterial disease. We hypothesized that genetic control of MR1 expression correlates with clinical outcomes of tuberculosis infection. We performed an MR1 candidate gene association study and identified an intronic single-nucleotide polymorphism (rs1052632) that was significantly associated with susceptibility to tuberculosis in a discovery and validation cohort of Vietnamese adults with tuberculosis. Stratification by site of disease revealed that rs1052632 genotype GG was strongly associated with the development of meningeal tuberculosis (odds ratio= 2.99; 95% confidence interval (CI) 1.64–5.43; P= 0.00006). Among patients with meningeal disease, absence of the G allele was associated with an increased risk of death (hazard ratio= 3.86; 95% CI 1.49–9.98; P= 0.005). Variant annotation tools using public databases indicate that rs1052632 is strongly associated with MR1 gene expression in lymphoblastoid cells (P= 0.004) and is located within a transcriptional enhancer in epithelial keratinocytes. These data support a role for MR1 in the pathogenesis of human tuberculosis by revealing that rs1052632 is associated with MR1 gene expression and susceptibility to tuberculosis in Vietnam.