Risk of chronic pulmonary emphysema from exposure to tobacco smoke varies widely from person to person, depending in part on the status of particular genes and acquired susceptibilities. Certain genes determine how cells activate and/or detoxify tobacco smoke products. We aimed to determine whether any genetic susceptibility exists in the development of emphysematous changes confirmed by chest computed tomography (CT). Genotypes of various enzymes involved in the activation or detoxification of tobacco smoke, epoxide hydrolase (EPHX1), cytochrome P450s (CYP1A1 and CYP2E1), glutathione S-transferases (GSTM1/P1/T1), and hemoxygenase-1 (HMOX1), were determined by PCR-based assays in a total of 235 heavy smokers (Brinkman index >/=400). They were divided into two groups according to the CT findings: 63 and 172 subjects with and without emphysematous changes, respectively. Although the allele frequency of any genetic polymorphism was not statistically different between the two groups, the frequency of the individuals having combination of the genotype representing very slow activity for epoxide hydrolase and at least one allele with large size of (GT)n repeats in the HMOX1 gene promoter region was higher in the subjects with emphysematous changes (p=0.03; odds ratio 2.8; 95% CI = 1.07-7.5) among the stratified individuals (age >/=51 years). These findings suggest that combination of several polymorphisms in the enzymes that activate or detoxify the tobacco smoke, such as EPHX1 and HMOX1, might be associated with its affects on the development of emphysematous changes of the lung.