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Acute liver failure (ALF) often requires multidisciplinary support. Higher hospital volumes have been associated with better outcomes for surgical procedures, but whether such a relationship exists for ALF has not been explored previously. In this study, our aim was to examine if hospital volume affects mortality from ALF. Using data from the Nationwide Inpatient Sample for the years 2001 to 2004, we identified cases by the presence of a primary discharge diagnosis of ALF (International Classification of Diseases, 9th revision, Clinical Modification code 570.x). Hospitals were divided into low-, medium-, and high-volume hospitals on the basis of 1 to 5, 6 to 20, and more than 20 annual ALF discharges. There were 17,361, 6756, and 1790 discharges with ALF from low-, medium-, and high-volume hospitals, respectively. There was no difference in adjusted mortality between low- and high-volume hospitals (odds ratio 0.94, 95% confidence interval 0.68-1.28). Teaching hospitals had a trend toward lower mortality among patients with hepatic encephalopathy (odds ratio 0.69, 95% confidence interval 0.47-1.01). High-volume centers had a higher rate of orthotopic liver transplantation (OLT) primarily because they were transplant centers, had better in-hospital post-OLT survival, and showed a trend toward a shorter time to OLT. In conclusion, patients with ALF receiving care at teaching hospitals and high-volume centers tend to be sicker. However, teaching hospitals and high-volume centers have equivalent in-hospital survival despite caring for this more severely ill cohort.