OBJECTIVE The case of a patient who developed toxic epidermal necrolysis (TEN) after treatment with rifaximin for hepatic encephalopathy is reported. CONCLUSIONS A 62-year-old Caucasian woman with a history of alcohol abuse arrived at the emergency room with complaints of abdominal pain and acute onset of jaundice, likely secondary to alcoholic hepatitis. Laboratory tests and multiple imaging studies conducted in the emergency department revealed signs of chronic liver disease and common bile duct dilation with ascites. At admission, she had low concentrations of serum sodium, serum chloride, serum creatinine, and serum albumin and elevated liver function test values. On hospital day 7, the patient developed an altered mental status, which was diagnosed as toxic metabolic encephalopathy, primarily hepatic in origin. The patient was given lactulose 20 g via nasogastric tube every 12 hours and rifaximin 400 mg orally every 8 hours. The patient received only two doses of the rifaximin before it was discontinued. On hospital day 27, oral rifaximin 550 mg twice daily was initiated. After 12 days of rifaximin therapy, the patient developed a diffuse, erythematous, maculopapular, and desquamating cutaneous reaction on her chest, arms, and legs. The suspected diagnosis was determined to be a severe cutaneous adverse drug reaction, possibly TEN. Use of the Naranjo et al. scale revealed that rifaximin was a possible cause of the reaction. Rifaximin was discontinued, and antihistamines and i.v. corticosteroids were initiated. The reaction completely resolved after one week. CONCLUSIONS A 62-year-old woman developed possible TEN after receiving rifaximin to treat hepatic encephalopathy.