2'-5'-Oligoadenylate synthetase 1 (OAS1) plays an important role in inflammatory immune reactions. OAS1 polymorphisms have been associated with increased susceptibility to various diseases. We investigated the association of polymorphisms in OAS1 with tuberculosis (TB).A total of 1215 TB cases and 1114 healthy controls were enrolled from two independent studies. Genotyping was conducted using the improved multiplex ligase detection reaction (iMLDR) method. Associations between OAS1 polymorphisms (rs2240190, rs1131454, 10,774,671 and 11,066,453) and TB risk were established based on distributions of allelic frequencies using different genetic models.Significant association was observed between rs10774671, rs1131454 and TB. In the initial study, the G allele of rs10774671 was a significantly protective factor against TB (P = 0.006) and the genotype of GG differed significantly between TB patients and controls under the codominant model (P = 0.008) after Bonferroni correction. In the validation study, we also observed that the rs10774671 G allele (P = 0.001) and GG genotype (P = 0.001) were associated with TB. In addition, we found that the rs1131454 G allele (P = 0.004) and GG genotype (P = 0.001) were protective against TB in the Chinese Han population.We report novel associations of polymorphisms in OAS1 with TB in the Chinese Tibetan and Han populations. Similar studies in different populations and functional studies are warranted to confirm our results.