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To describe the mechanisms of severe hepatocellular injury with apoptosis in 2 patients receiving hepatitis C virus (HCV)-796.HCV-796 is a hepatitis C polymerase inhibitor approved by the US Food and Drug Administration for a phase 2 study of the treatment of hepatitis C in combination with PEG-Interferon and ribavirin.The injury occurred after more than 12 weeks of treatment, with a >20-fold increase in serum alanine aminotransferase and aspartate aminotransferase, and a marked increase in total (and direct) bilirubin in the absence of cholestasis. There was no evidence of autoimmune or viral hepatitis. Involvement of the mitochondrial apoptotic pathway was demonstrated by (1) release of cytochrome C into the cytosol; (2) association of cytochrome C with apoptotic protease activating factor-1 in the cytosol; (3) activation of initiator caspase 9; (4) activation of effector caspase 3; (5) increased serum caspase-3 cleaved cytokeratin-18 peptide; (6) nuclear fragmentation; (7) mitochondrial structural abnormalities; (8) expression of light chain 3 B, an indicator of autophagy; (9) probable autophagy of mitochondria by autophagosomes; and (10) probable phagocytosis of apoptotic hepatocytes by activated macrophages. Immunoglobulin G immune complexes were identified in the hepatocytes and localized to the endoplasmic reticulum and Golgi of these patients after the drug-induced liver disease, reflecting a primary or secondary target. Hepatitis C treatment was discontinued at weeks 15 and 19 in patients 1 and 2, respectively. After more than 6 months off the medication, both patients normalized the serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin with undetectable HCV RNA.HCV-796 may cause severe hepatocellular injury and apoptosis, with a marked immune reaction in susceptible patients.