Background <p>Studies have reported inconsistent findings regarding the association between the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) and the risk of acute pancreatitis (AP). In this study we aimed to determine whether ACEis and ARBs are associated with an increased risk of AP.</p> Methods <p>This population-based, retrospective cohort study utilized TriNetX to compare AP incidence among new users of ACEIs and ARBs, with dihydropyridine calcium channel blockers (dCCBs) as an active comparator. Propensity matching in a 1:1 ratio matched patients based on demography, comorbidities, and medications. Cox proportional hazard models were utilized to estimate hazard ratios (HRs).</p> Results <p>The study cohort consisted of 3,749,482 ACEI users, 2,444,549 ARBs, and 3,735,923 dCCBs. ACEIs were associated with a significantly increased risk of AP compared to ARBs, with a HR of 1.32 (95% CI: 1.30–1.34). The increased risk of AP remained stable for up to five years, with hazard ratios (HRs) ranging from 1.32 to 1.57. These findings were consistent across secondary and sensitivity analyses. In contrast, ARB users had a significantly lower risk of AP at all follow-up time points.</p> Conclusion <p>ACEI use is associated with an increased risk of AP compared to dCCBs, while ARB use is associated with a lower risk of AP.</p>