Objective To investigate the relationship of smoking, the gene polymorphisms of heine oxygenase-1, tumor necrosis factor-α, and human β-defensin-1 with chronic obstructive pulmonary disease (COPD). Methods A case-control study was held to compare the genotype frequency distribution of heine oxygenase-1, tumor necrosis factor-α, human β-defensin-1 by PCR -RFLP method and to analyze the relationship among them. Results The L allele gene frequency of heine oxygenase-1 was 23.44% in COPD group and 10.71% in control group with significant difference(P＜0.05). The heterogenesis gene frequency of tumor necrosis factor-α in COPD group and control group were 18. 24% and 7.53% (P＜0.01). The heterogenesis gene frequency of human β-defensin-1 was 14.28% in COPD group and 5.00% in control group with significant difference(P＜0. 01). Conclusions Smoking is a risk factor for COPD. Genetic polymorphisms of heme oxygenase-1, tumor necrosis factor-α, human β-defensin-1 are related with the development of COPD.