AIM: To explore whether cyclooxygenase 2 (COX-2) -765G＞C polymorphism is associated with susceptibility of colorectal cancer (CRC) and to evaluate the risk of colorectal cancer in relation to environmental exposures and polymorphism.METHODS: We conducted a case-control study of 137 patients with colorectal cancer and 199 cancer-free controls in northeast China. Multivariate logistic regression analysis was performed to calculate the adjusted odds ratio (OR) and 95% confidence interval (95% CI).RESULTS: The -765G＞C polymorphism was not independently associated with CRC risk. However, risk associated with the polymorphism differed by smoking and body mass index (BMI). Smoking and BMI associated risks were stronger among those with -765GG genotype, showing that smokers had a 2.682-fold greater risk of CRC than nonsmokers (51/43 vs 68/126, P = 0.006). Compared to those with a normal body mass index (BMI 18.5-22.9), those with overweight (BMI 23-24.9) had a 3.909-fold higher risk of CRC (OR = 3.909, 95% CI = 2.081-7.344; P ＜ 0.001), while those with obesity (BMI ＞ 25) had a 2.031- fold higher risk of CRC (OR = 1.107, 95% CI = 1.107-3.726; P = 0.022).CONCLUSION: Although COX-2 -765G＞C polymorphism is not associated with an increased risk of CRC, -765GG genotype appears to be related to an increased risk in the presence of smoking and higher BMI.