Cytochrome P450 (CYP) 2C19 is expressed in vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs), which play a crucial role in either the detoxification or inactivation of potential carcinogens, or the bioactivation of some environmental procarcinogens to reactive DNA-binding metabolites. And smoking is a major risk factor for lung cancer. The purpose of this study is to explore the relationship between the interaction of CYP2C19*3 polymorphism and smoking and lung cancer in a Chinese population. In a Chinese case-control study of lung cancer patients (n=420) and healthy controls (n=420), we investigated the roles of CYP2C19*3 polymorphism in lung cancer risk using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. We found that the frequency of CYP2C19 (*)3 (AG + AA) genotype was significantly higher in lung cancer patients than that in control subjects (14.28 % versus 4.76 %; P<0.001). Multivariable logistic regression analysis showed that after adjustment of other risk factors, the A allele of CYP2C19*3 remains significantly associated with lung cancer. We also found that there was a significant interaction between CYP2C19 (*)3 and smoking in increasing the risk for lung cancer (OR 5.121, 95 % confidence interval [CI] 4.321-10.124; P=0.001). The interaction between CYP2C19 (*)3 polymorphism and smoking plays an important role in the mechanism of lung cancer in Chinese population.