Hepatic dysfunction occurs in up to 10% of patients with sickle cell crisis; however, hepatic failure is quite unusual. Cocaine hepatotoxicity has recently been recognized in humans with liver biopsies showing varying patterns of necrosis. Most patients reported with cocaine intoxication have rhabdomyolysis with renal failure, and half of the cases have been fatal. A patient with concomitant sickle cell crisis and cocaine intoxication presented with hepatic failure, coagulopathy, and encephalopathy. Transjugular liver biopsy showed focal areas of confluent necrosis and large areas of collapse. Cocaine intoxication should be considered in the differential diagnosis of hepatic failure in patients with sickle cell anemia.