Chronic obstructive pulmonary disease (COPD) is considered a complex genetic disorder and it is expected that many genes play a role in the pathogenesis of this disease. Previous studies have reported that several variations within the interleukin (IL)-18 gene promoter region have been associated with different inflammatory diseases such as asthma. However, the association of IL-18 promoter polymorphisms with COPD has not been studied yet. We then performed a prospective casecontrol study to explore this association in male smokers of Chinese Han people. Our study recruited 112 COPD cases and 105 healthy controls matched for age. The genotyping of IL-18 promoter polymorphisms (-607 C/A and -137 G/C) was performed using TaqMan single nucleotide polymorphism genotyping assays. The frequencies of the alleles and genotypes in patients and controls were compared. We found that the frequency of IL-18 -607 C allele was significantly increased in patients with COPD (odds ratio (OR)=1.48, 95% confidence interval (CI)=1.012.15, P=0.04). The frequency of IL-18 -607 C allele was significantly higher in the GOLD (Global initiative for Obstructive Lung Disease) 34 group compared with the GOLD 12 group (OR=2.06, 95% CI=1.213.51, P=0.01). There were no significant differences in the frequencies of the alleles and genotypes of IL-18 -137 G/C polymorphism between the patients and healthy smokers or between GOLD 34 group and GOLD 12 group. Our study revealed that the IL-18 -607 C/A polymorphism was associated with COPD susceptibility and severity of airflow limitation in male smokers of Chinese Han people.