Recent studies have proposed that susceptibility to chronic obstructive pulmonary disease (COPD) might be related with the polymorphisms of some genes encoding antioxidant enzymes, such as heme oxygenase-1 (HOX-1) and microsomal epoxide hydrolase (mEPH). We examined these polymorphisms in 256 patients with COPD and 266 healthy smokers from Han population in Southwest China. The frequencies of each allele were compared both individually and in combination between patients and controls. Polymorphisms of HOX-1 gene could be grouped into three classes: S (<or=25 repeat), M (26-31 repeat), and L (>or=32 repeat). The allele frequencies of class L and the genotypic frequencies of the group with L were significantly higher in COPD than in controls. Our findings also showed that the proportion of slow mEPH activity was significantly higher in COPD than in controls. Conversely, the proportion of fast mEPH activity was significantly lower in COPD. In combined analysis, the frequency of the individuals having at least one L allele in the HOX-1 gene promoter and slow or very slow activity genotype for mEPH was higher in COPD than in control. Genetic polymorphisms in HOX-1 and mEPH genes are associated with the development of COPD in Southwest China.