Objective To study the role of myeloperoxidase (MPO) in the relationship between smoking and risk of pancreatic cancer. Methods A case-control study was adopted in the present study. Totally 71 patients with newly diagnosed pancreatic ductal adenocarcinoma (pathologically confirmed) and 71 age- and sex-matched healthy persons were included. All the subjects were interviewed using a self-designed questionnaire concerning the age, sex, body mass index (BMI), smoking, alcohol consumption, and history of diabetes mellitus. The venous blood samples were collected from patients before treatment and enzyme-linked immunosorbent assay was used to measure the plasma MPO; the subjects were divided into high and low MPO groups based on the median MPO value of controls. Unconditional logistic regression model was used to study the relationship of smoking with risk of pancreatic cancer, risk of pancreatic cancer with high plasma MPO, and risk of pancreatic cancer with low plasma MPO. Results After adjusted for age, sex, alcohol consumption, and BMI, smoking significantly increased the risk of pancreatic cancer (OR=2.74, 95%CI: 1.12-6.74; P=0.028). Besides, smoking was also significantly associated with increased risk of pancreatic cancer with high plasma MPO (>196 IU/L) (OR=3.81, 95%CI: 1.17-12.44; P=0.026), and was not significantly associated with the risk of pancreatic cancer with low plasma MPO (≤196 IU/L) (OR=2.51, 95%CI: 0.82-7.72; P=0.108). Conclusion Smoking may increase the risk of pancreatic cancer. High plasma MPO level may play an important role in the relationship between smoking and risk of pancreatic cancer.