This study aimed to investigate the correlation between SERPINA1 single nucleotide polymorphism (SNP) rs17580, smoking, and pulmonary tuberculosis (TB). A total of 420 TB patients (observation group) and 640 patients without pulmonary disease (control group) were randomly included. The frequencies of different genotypes were counted in both groups, and the correlation between SNP genotypes and the occurrence of TB was analyzed. Statistical models were performed to analyze the correlation between rs17580 and TB and the correlation between rs17580. The frequencies of genotypes TT, TA, and AA at the rs17580 locus in patients with TB were not statistically different from those in the control group ( P > 0.05 ), and the distributions of the two groups were in accordance with the Hardy–Weinberg equilibrium law. rs17580 was analyzed in dominant, recessive, and codominant models, exhibiting no statistical difference ( P > 0.05 ). There was no significant difference among the three genotypes in the 1–5 typing (χ2 = 1.034, P = 0.998 ), and the difference between T and C was not statistically significant (χ2 = 0.012, P = 0.999 ). There was a significant difference between the three genotypes between the smoking group and the nonsmoking group in TB patients ( P < 0.05 ). There was no significant difference among three genotypes in the alcoholic group and the nonalcoholic group in TB patients ( P > 0.05 ). There was no statistical difference in the time to cure among the 3 genotypes in TB patients ( P > 0.05 ). A type mutation of rs17580 in the SERPINA1 gene was strongly associated with a higher risk of development of TB in smoking patients.