Acute pancreatitis is a most serious complication following endoscopic retrograde cholangiopancreatography (ERCP). Previous meta-analyses and randomized controlled trials have shown conflicting results regarding the preventive efficacy of somatostatin or octreotide for this complication. The aim of this study was to resolve these conflicts. A standardized comprehensive literature search was performed through September 2009. Depending on heterogeneity of outcomes, either random-effects model (REM) or fixed-effects model (FEM) was applied to calculate pooled estimates of drug efficacy. Seventeen studies, including 3818 participants, met the inclusion criteria. Analysis of somatostatin and octreotide trials showed that these drugs prevented post-ERCP pancreatitis (pooled risk ratio [95% confidence interval; CI], 0.63 [0.42-0.96] in REM. Pooled risk ratios [95% CI] of each subgroup were: 0.52 [0.30-0.90] for somatostatin in REM; 0.30 [0.17-0.53] for high-dose somatostatin infused over 12 h in FEM; 0.27 [0.13-0.52] for bolus somatostatin in FEM; 0.35 [0.15-0.82] for pancreatic duct (PD) injection with somatostatin in FEM; 0.33 [0.16-0.70] for biliary sphincterotomy (BS) with somatostatin in FEM; 0.53 [0.24-1.17] for intention-to-treat (ITT) analysis with somatostatin in REM; 0.42 [0.20-0.90] for high-dose octreotide in FEM; 0.61 [0.27-1.35] for PD injection with octreotide in FEM; 0.64 [0.32-1.29] for BS with octreotide in FEM; and 0.83 [0.34-2.03] for ITT analysis with octreotide in REM. Somatostatin and high-dose octreotide may prevent post-ERCP pancreatitis. The preventive efficacy of somatostatin is more prominent in cases of PD injection, or BS, or high-dose administration over 12 h, or bolus injection.