Niacin (vitamin B3) is available as a prescription medication and over-the-counter supplement. Although it is well known for its vasodilatory effect, it has also been associated with mild hepatotoxicity and, rarely, acute liver failure. We present the case of a 74-year-old Hispanic woman who developed acute liver failure (anicteric encephalopathy and coagulopathy) after her home dose of immediate-release niacin was replaced with an extended-release formulation during an inpatient hospital stay. This is the first reported case of niacin toxicity associated with a histopathologic finding of diffuse microvesicular steatosis. This unique phenotype strongly implicates mitochondrial impairment as a mechanism of niacin-induced hepatotoxicity.