Genetic susceptibility to the development of chronic obstructive pulmonary disease (COPD) might depend on variation in the activities of enzymes that detoxify cigarette smoke products, such as microsomal epoxide hydrolase (mEPHX) and glutathione S-transferase (GST). It was investigated whether polymorphisms in these genes had any association with susceptibility to COPD and COPD severity. The genotypes of 184 patients with COPD and 212 control subjects were determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis of the mEPHX, GSTM1, GSTT1 and GSTP1 genes. All subjects were smokers or exsmokers. The proportion of GSTM1-null genotypes was significantly higher in patients with COPD than in control subjects (61.4 versus 42.5%). No differences were observed in the frequency of polymorphic genotypes for mEPHX, GSTT1 and GSTP1. During combined analysis of genetic polymorphisms for mEPHX, GSTM1 and GSTP1, it was found that there are strong indicators for susceptibility to COPD (genotype combination with at least one mutant mEPHX exon-3 allele (histidine 113), GSTM1 null and homozygous for the GSTPI isoleucine 105 allele). The frequencies of homozygous mutant alleles of mEPHX exon 3 and the GSTMI-null genotype were significantly higher in patients with severe COPD (forced expiratory volume in one second of <35% of the predicted value). It is proposed that the combination of genetic variants including at least one mutant microsomal epoxide hydrolase exon-3 allele and glutathione S-transferase M1-null and homozygous isoleucine 105 glutathione S-transferase P1 genotypes are significant indicators of susceptibility to chronic obstructive pulmonary disease in the Taiwanese population. In addition, the homozygous variant of microsomal epoxide hydrolase exon 3 and the glutathione S-transferase M1-null genotype are independent risk factors for developing severe chronic obstructive pulmonary disease.