Objective To assess the efficacy of proton pump inhibitors for preventing post-endoscopio retrograde cholangiopancreatography (post-ERCP) pancreatitis and hyperamylasemia. Methods A total of 250 patients, who underwent successful ERCP, were randomized into control group (n = 126) or treatment group (n=124) after ERCP. All patients received octreotide, the patients in treatment group received omeprazole 40 mg i. v. every 12 h; while the patients in control group received same amount of normal saline. The serum level of amylase at 4, 24 h and TNF-a were determined and the incidence of post-ERCP pancreatitis was documented. Results There were no differences in age, sex and proportion of therapeutic procedures performed between the two groups. The serum amylase and TNF-a levels at 4, 24h were (221 ± 31) U/L, (181 ±39) U/L, (0.264 ±0.052) ng/ml and (0.257 ±0.071) ng/ml in treatment group, respectively; which were significantly lower than (272 ±32) U/L, (227 ±30) U/L, (0. 372 ±0.047) ng/ml and (0.422 ±0.026) ng/ml in the control group (P<0.05). The incidence of pancreatitis in proton pump inhibitors group was 1.6%, which was significantly lower than that in control group (5.6% , P = 0. 04) . Conclusions Combination of proton pump inhibitors and octreotide could effectively decrease the incidence of post-ERCP hyperamylasemia and pancreatitis.