Objectives Tumor necrosis factor-α (TNF-α) may play an important role in host's immune response to mycobacterium tuberculosis (M. Tuberculosis) infection. This study was to investigate the association of TNF-α gene polymorphism with pulmonary tuberculosis (TB) among patients with coal worker's pneumoconiusis (CWP). Methods A case-control study was conducted in 113 patients with confirmed CWP complicated with pulmonary TB and 113 non-TB controls with CWP. They were matched in gender, age, job, and stage of pneumoconiosis. All participants were interviewed with questionnaires and their blood specimens were collected for genetic determination with informed consent. The TNF-α gene polymorphism was determined with polymerase chain reaction of restriction fragment length polymorphism (PCR-RFLP). Frequency of genotypos was assessed for Hardy-Weinberg equilibrium by chi-square test or Fisher's exact probability. Factors influencing the association of individual susceptibility with pulmonary TB were evaluated with logistic regression analysis. Gene-environment interaction was evaluated by a multiplicative model with combined OR. All data were analyzed using SAS version 8.2 software. Results No significant difference in frequency of the TNF-α-308 genotype was found between CWP complicated with pulmonary TB and non-TB controls (2,2=5.44,P=0.07). But difference in frequency of the TNF-α-308 A allele was identified between them (X2=5.14, P=0.02). No significant difference in frequencies of the TNF-α-238 genotype and allele (P=0.23 and P=0.09, respectively) was found between cases and controls either, with combined (GG and AA) OR of 3.96 (95% confidence interval of 1.30～12.09) at the -308 locus of the TNF-α gene, as compared to combination of the TNF-α-238 GG and TNF-α-308 GG genotypes. Multivariate-adjusted odds ratio of the TNF-α-238 GG and TNF-α-308 GA genotypos was 1.98 (95% CI of 1.06～3.71) for risk for pulmonary TB in patients with CWP. There was a synergic interaction between the TNF-α-308 GG genotype and body mass index (OR=4.92), as well as an interaction between the TNF-α-308 GG genotype and history of BCG immunization or history of TB exposure. And, the interaction of the TNF-α-238 GG genotype and history of BCG immunization or TB exposure with risk for pulmonary TB in them was also indicated. Conclusions TNF-α-308 A allele is associated with an elevated risk for pulmnonary TB, whereas TNF-α-238 A allele was otherwise.