Background and Aims: The World Health Organization lists .500 medications as potentially associated with acute pancreatitis (AP) based on case reports. Among these agents are several very commonly prescribed medications. The aim of the present study was to determine the risk of pancreatitis associated with use commonly prescribed medications. Methods: We conducted a retrospective comparative cohort study on data from an integrated healthcare system in Southern California. We identified patients that filled prescriptions for any of the following agents from 2006 2011: hydrochlorothiazide (HCT), lisinopril (LIS), metformin (MET), omeprazole (OME), simvastatin (SIM). Patients with history of acute pancreatitis within 6 months prior to initiating medication were excluded. Incidence of first inpatient acute pancreatitis (icd9 577.0) for each medication-cohort was calculated based on persontime at risk with patients censored upon development of pancreatitis, discontinuation of medication, health plan disenrollment, death or study conclusion. Ageand gender-adjusted incidence rate-ratios were calculated for each medication using the Healthplan membership, exclusive of aforementioned medication use, as the reference population (Poisson regression). Results: Table 1 lists the attributes of the study cohorts that ranged in size from 276,190 patients for MET to 651,994 patients for SIM. The reference population consisted of 1.5 million Healthplan members. Average follow-up in the study cohorts ranged from 4.7-5.0 years per patient with a total of 1.3-3.8 million person-years of follow-up. Overall incidence of AP in the reference population was 0.16/1000 person-years. Incidence of AP in the study cohorts was as follows: HCT 1.36/1000 person-years, p,0.0001; LIS 1.71/1000 personyears, p,0.0001; MET 1.51/1000 person-years, p,0.0001; OME 1.91/1000 person-years, p,0.0001; SIM 0.99/1000 person-years, p,0.0001. Age, race and gender-adjusted incidence rate ratios for AP were as follows: HCT 4.1 (95% CL 2.8,6.0), LIS 5.3 (3.6,7.8), MET 4.9 (3.3, 7.2), OME 6.6 (4.5,9.7), SIM 3.1 (2.1,4.5). Conclusions: An increased risk of acute pancreatitis was observed among patients taking these 5 commonly prescribed medications. Further investigation is needed to determine whether this association is a class-effect as well as evaluate the effects of additional potential residual confounders on risk of acute pancreatitis.