Acetaminophen-induced liver failure is the most common cause of acute liver failure in the United States. The exact mechanism of acute liver failure secondary to acetaminophen toxicity is unknown, although a presumed mechanism of hepatocellular necrosis involving the accumulation of a toxic metabolite (N-acetyl-p-benzoquinoneimine) has been postulated. A 62-year-old woman with a history of a suicide attempt was brought to the emergency department at ∼12 hours post acetaminophen overdose. The patient presented with an acetaminophen level of 284 mcg/mL and with profound hypothermia (31°C). Liver function tests and coagulation studies were normal. Within 24 hours of presentation, the patient was normothermic, had received seven oral doses of N-acetylcysteine, and had an acetaminophen level of <5 mcg/mL. The patient was discharged from the intensive care unit at 96 hours post admission in stable condition with no evidence of hepatic injury. No further treatment with N-acetylcysteine was required. Despite a toxic acetaminophen level, this patient did not suffer any hepatic injury. Hypothermia may have attenuated the production of N-acetyl-p-benzoquinoneimine by depressing the cytochrome P450 system, allowing accumulation of the parent drug rather than toxic metabolites. This case report suggests that hypothermia may have protected the liver of a patient presenting with acetaminophen toxicity and supports further investigation into the potential therapeutic role of induced hypothermia during acetaminophen toxicity.