Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by persistent airflow limitation. Smoking, occupational exposures, air pollution, and genetics are all risk factors. In the present study, we detected the cytochrome P4501A1 gene (CYP1A1) MspI polymorphism and the tumor necrosis factor alpha (TNFα)-308 single nucleotide polymorphism in COPD patients, and investigated their associations with smoking and COPD susceptibility in Inner Mongolia. A total of 101 COPD patients and 80 controls were enrolled in the study. The polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). CYP1A1 MspI allele frequencies were significantly different between COPD patients and controls (P = 0.033). COPD susceptibility was higher in subjects with the m2 allele compared to subjects with the m1 allele [odds ratio (OR) = 2.531, 95% confidence interval (CI) = 1.297-4.940, P = 0.006]. Significant differences were observed in the TNFα-308 genotype and allele distributions between COPD patients and controls (P = 0.006 and P = 0.003, respectively). Compared to subjects with the GG genotype, subjects with GA+AA genotypes had higher COPD risk (OR = 3.639, 95%CI = 1.576-8.403, P = 0.002). The TNFα-308 polymorphism differed between smoking and non-smoking COPD patients and controls (P = 0.047 for genotype and P = 0.030 for allele). In conclusion, the CYP1A1 MspI and TNFα-308 polymorphisms were associated with COPD susceptibility. Furthermore, of the two polymorphisms, only TNFα-308 may exert an interaction with smoking.