Microsomal epoxide hydrolase (EPHX1) is an enzyme involved in the detoxification the products of smoking and is proposed to be a genetic factor for the development of chronic obstructive pulmonary disease (COPD). Two functional polymorphisms of EPHX1, T113C and A139G, have been analyzed in numerous studies to assess the COPD risk attributed to these variants. However, the conclusions were controversial. We performed a comprehensive meta-analysis to clarify these findings. A total of 24 studies comprising 8,259 COPD patients and 42,883 controls were included. The overall results showed that the EPHX1 113 mutant homozygote was significantly associated with an increased risk of COPD (OR, 1.33; 95% CI, 1.06-1.69). The subgroup analyses demonstrated this association in Caucasian individuals (OR, 1.61; 95% CI, 1.12-2.31) but not in Asian individuals. The 139 mutant heterozygote was significantly associated with a decreased risk of COPD in Asian populations (OR, 0.82; 95% CI, 0.68-0.99) but not in Caucasian populations. Pooled analyses revealed that the extremely slow (OR, 1.77; 95% CI, 1.23-2.55) and slow EPHX1 enzyme activity (OR, 1.44; 95% CI, 1.13-1.85) were associated with an increased risk of COPD, while the fast enzyme activity was not associated with a decreased risk of COPD. The stratified analysis demonstrated this association in Caucasian but not in Asian individuals. Furthermore, a modest difference in the risk of COPD was observed between the subgroups by using the cigarette smokers or the non-smokers as controls. A significant correlation between the two functional polymorphisms, T113C and A139G, of the EPHX1 gene and the enzyme activity and the individual's susceptibility to COPD was noted. In addition, the results supported a contribution of EPHX1 to the aetiology of COPD.