Objective: To investigate the preventive measures of acute pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP). Methods: Within the period of July 2010 to November 2012, 100 patients undergoing ERCP were randomly designated to observation group or control group with 50 cases in each group. After ERCP procedure, the patients in observation group received the combination treatment of somatostatin (octreotide 0.1 mg/8 h subcutaneous injection for 24 h) and proton pump inhibitor (pantoprazole 40 mg/d intravenous drip for 2 d), while those in control group were given normal saline instead. The serum levels of amylase at 3, 12 and 24 h after ERCP, and incidences of post-ERCP acute pancreatitis between the two groups were compared. Results: The general data between the two groups were comparable. The serum levels of amylase in observation group at 3, 12 and 24 h after ERCP were all significantly lower than those in control group (all P<0.05). The incidences of hyperamylasemia at 12 and 24 h after ERCP and post-ERCP acute pancreatitis in observation group were all significantly lower than those in control group (18% vs. 42%; 8% vs. 22%; 2% vs. 16%) (all P<0.05). Conclusion: The combination use of somatostatin and proton pump inhibitor can reduce the incidences of post-ERCP hyperamylasemia and pancreatitis, so it is safe and effective for prevention of post-ERCP pancreatitis.