Coronary artery disease (CAD) has a high mortality rate in several countries. Interleukin (IL)-18 has been previously correlated with atherosclerotic plaque rupture. In this case-control study, the relationship between -607A/C and -372C/G promoter polymorphisms in IL-18 and risk of CAD development was investigated. A total of 326 CAD patients were consecutively recruited from the First Hospital of Yulin between March 2013 and May 2015. The IL-18 -607A/C and -372C/G polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Patients with CAD had a higher body mass index, a history of hypertension or diabetes (all P < 0.001), cigarette smoking habit (P = 0.002); as well as higher plasma total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels (all P < 0.001) and lower high-density lipoprotein cholesterol (P < 0.001) levels compared to the control subjects. Unconditional logistic regression analysis revealed significant correlation between the CC genotype of IL-18 -607A/C and CAD development, compared to the AA genotype [adjusted odds ratio (OR) = 2.42; 95% confidence interval (CI) = 1.52-3.89; P < 0.001]. The recessive model showed a significant association between the CC genotype of IL-18 -607A/C and an increased risk of CAD, compared to the AA+AC genotype (OR = 2.51, 95%CI = 1.65-3.85). However, IL-18 -372C/G did not contribute to the risk of glioma development in the co-dominant, dominant, and recessive models. Therefore, the IL-18 -607C/A polymorphism was significantly correlated with the risk of CAD development.