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Context Acute pancreatitis is one of the most common causes for acute hospitalization related to digestive disease. Objectives This study aimed to examine regional variation in national healthcare expenditure for management of acute pancreatitis. Methods The Nationwide Inpatient Sample from 2010 was utilized to examine hospitalizations for acute pancreatitis. Total costs per hospitalization were calculated from charges using a cost-to-charge ratio and adjusted for suspected cost determinants from multivariable regression analysis. States were then ranked by costs and divided into tertiles for evaluation of outcome measures, including in-hospital mortality. Results Acute pancreatitis accounted for 288,597 hospitalizations in 2010. Regional variation was demonstrated after adjustment with a mean cost per hospitalization of $12,446.48. There was a difference of $4,870 per hospitalization between states in low cost and high cost tertiles. Highcost states had a greater use of mechanical ventilation and infusion of supplemental nutrition (p0.0001). Despite these differences, inhospital mortality remained similar across cost tertiles p=0.44). Several low-cost states were identified in traditionally high-cost regions. Conclusions Significant regional variation in costs for acute pancreatitis persisted after adjusting for patient demographics, hospital characteristics and case mix variables. This variation suggests opportunities for increasing efficiency without compromising quality of care for acute pancreatitis.