OBJECTIVES: To examine the association between incretin-based therapies and the risk of pancreatitis. METHODS: We searched Medline, Embase, CENTRAL and ClinicalTrials.gov to identify randomized controlled trials (RCTs), non-randomized clinical trials, cohort studies, and case-control studies of adults with type 2 diabetes mellitus that compared glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors against placebo or active anti-diabetic medications. Trained reviewers, working in pairs, independently screened for eligible studies, assessed risk of bias, and extracted data. RESULTS:  We included 59 studies (n=348,624), consisting of 55 RCTs (n=33,350) and 4 observational studies (n= 315,274). Pooled estimates of 55 RCTs (at low or moderate risk of bias involving 37 pancreatitis events, raw event rate 0.11%) did not suggest increased risk of pancreatitis between incretin agents versus control (Peto OR 1.11, 95% CI 0.57 to 2.17). Estimates by type of incretin agents suggested similar results (GLP-1 agonists vs. control: OR 1.05, 95% CI 0.37 to 2.94; DPP-4 inhibitors vs. control: OR 1.06, 95% CI 0.46 to 2.45). Three retrospective cohort studies (moderate to high risk of bias involving 1466 pancreatitis events, raw event rate 0.47%) also did not suggest increased risk of pancreatitis associated with either exenatide (adjusted OR 0.93, 95% CI 0.63 to 1.36 in one study, adjusted hazard ratio (HR) 0.9, 95% CI 0.6 to 1.5 in another) or sitagliptin (adjusted HR 1.0, 95% CI 0.7 to 1.3). However, a matched case-control study with moderate risk of bias suggested that the use of either sitagliptin or exenatide was associated with increased odds of acute pancreatitis (adjusted OR 2.07, 95% CI, 1.36 to 3.13). CONCLUSIONS: The available evidence suggests that the risk of pancreatitis in patients using incretin agents is very low, and does not support for the hypothesis that incretins increase the risk of pancreatitis.