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Coronary artery disease (CAD) is a complex multifactorial and polygenic disorder where multiple environmental and genetic factors are involved simultaneously. The purpose of this study was to explore the relationship between the interaction of cyclooxygenase-2 (COX-2) gene polymorphism and smoking and CAD in a Uighur population.Using a case-control study of Chinese Uighur CAD patients (n = 430) and healthy controls (n = 470), we investigated the roles of G-765C polymorphism in the COX-2 gene (PTGS2) by the use of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.The PTGS2 GG genotype was significantly more prevalent in CAD patients (84.6% vs. 78.3%; p = 0.014). Multiple logistic regression analysis showed two independent risk factors: smoking (OR 1.89, 95% CI 1.01–5.24; p = 0.008) and hypertension (OR 2.73, 95% CI 1.59–7.21; p = 0.001). Moreover, there was a synergistic effect between smoking and the PTGS2 polymorphism and the occurrence of CAD (interaction p = 0.009). The odds ratio (OR) estimated by the combined analysis of the PTGS2 GG genotype and smoking history (OR 4.09, 95% CI 2.7–9.3) was markedly higher than that estimated separately from the PTGS2 GG genotype (OR 1.28, 95% CI 0.8–1.9) or smoking (OR 2.51, 95% CI 1.5–5.7) alone. Plasma 6-keto-PGF1α, a stable metabolite of PGI2, was lower in individuals with the PTGS2 GG genotype (p < 0.05). Smoking could further lower plasma 6-keto-PGF1α concentrations in GG genotype carriers than non-smokers, especially in patients with CAD.The PTGS2 polymorphism and smoking were synergistically and significantly associated in Chinese Uighur patients with CAD.