Abstract: Objectives To evaluate the clinical effect of indomethacin administered at different time points on the prevention of post-ERCP pancreatitis. Methods Totally 288 patients with common bile duct stones who received ERCP in our hospital's gastroenterology department from December 2014 to December 2015 were selected in this study. They were randomly divided into indomethacin group (n=144) and control group (n=144). Meanwhile the indomethacin group were further grouped into group A (n=36, administered 2 hours before the surgery), group B (n=36, administered 30 minutes before the surgery), group C (n=36, administered 30 minutes after the surgery) and group D (n=36, administered 2 hours after the surgery). Group E was the control group. Then we compared the incidences of hyperamylasemia and PEP after operation between different groups. Results There was no significant difference in patients' age, sex, serum amylase level before operation between groups (P> 0.05). The incidence of postoperative pancreatitis in indomethacin group was 9.0% which was significantly lower than that of the control group's 18.8% (P=0.017). Meanwhile the occurrence rates of PEP in group A, group B, group C, group D were 13.9%, 5.6%, 8.3% and 8.3% respectively, and the difference was not statistically significant (P> 0.05). But the occurrence rates of hyperamylasemia in group B and group C were significantly lower than those of group A and group D. Conclusion Treated with indomethacin at different points can all reduce the incidence of PEP; indomethacin administered at 30 minutes before the surgery or 30 minutes after the surgery will reduce the incidence of postoperative hyperamylasemia.