Sevoflurane, a halogenated anesthetic, is associated with mild aminotransferase elevations but does not tend to cause clinically significant hepatotoxicity. We report a rare case of severe hepatic necrosis following exposure to sevoflurane during surgery. A 37-year-old man presented with nausea, vomiting, abdominal pain, and jaundice on the third postoperative day after an abdominal wall mass resection. Laboratory tests showed markedly elevated aminotransferase levels, hyperbilirubinemia, and coagulopathy. His viral hepatitis and human immunodeficiency virus (HIV) serologies were negative for acute infection, and his Epstein-Barr virus (EBV) and cytomegalovirus (CMV) serologies were suggestive of recent EBV infection and remote CMV infection. Antinuclear antibody and anti smooth muscle antibody screens were negative. Ceruloplasmin and serum copper values were in the normal range. The histopathological findings included an acute centrilobular cholestatic hepatocellular injury compatible with the clinical history of acute drug-induced hepatotoxicity. The patient improved with conservative management. Unlike other halogenated anesthetics, proposed mechanisms of sevoflurane hepatotoxicity include production of compound A, increased cytosolic free Ca(2+), and activation of free radical metabolizing enzymes. The patient was likely susceptible to toxicity due to an underlying EBV infection and a probable history of exposure to halogenated anesthetics. Sevoflurane is generally considered to be relatively safe for subjects with mild liver dysfunction, in comparison with other halogenated anesthetics. However, this case suggests that sevoflurane can lead to severe life-threatening hepatic necrosis in at-risk individuals.