INTRODUCTION: Trimethoprim-Sulfamethoxazole induced DRESS requiring Liver Transplant. CASE DESCRIPTION/METHODS: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome can occur in the setting of DILI and is indicative of an idiosyncratic reaction which is now increasingly recognized with antibiotic use. The pathophysiology of DRESS is incompletely understood, but thought to involve reactivation of herpes viruses, genetic deficiency of detoxifying enzymes and associations between human leukocyte antigen (HLA) and drug hypersensitivity, leading to overwhelming response by the immune system. DILI-associated DRESS is rarely refractory to medical treatment requiring liver transplantation. We report a case of a 21-year-old male who presented with acute liver injury preceded by two weeks of nausea and vomiting. Prior to onset of symptoms, he was started on trimethoprim-sulfamethoxazole (TMP-SMX) for penile discharge. On presentation, he had a fever of 100.5°F, right upper quadrant abdominal pain and an erythematous rash involving upper extremities and later spreading to his face, trunk and lower extremities. Review of his records showed normal aspartate aminotransferase (AST) and alanine aminotransferase (ALT) from a week prior to admission but repeat labs showed an AST of 1480, and ALT of 764. He was found to have an elevated prothrombin time (PT) and INR but no signs of encephalopathy. Complete blood count with differential showed peripheral eosinophilia. Workup for infectious, autoimmune, and metabolic etiologies returned negative and broad-spectrum antibiotics were started for recurring fevers. European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) score of 4-5 placed the patient as ‘Probable DRESS’ with the most likely culprit being TMP-SMX. Skin punch biopsy showed subacute spongiotic dermatitis with eosinophils consistent with DRESS. Due to worsened liver function a liver biopsy was obtained which showed lobular hepatitis with sub-massive hepatocyte necrosis and increased eosinophils. The patient developed encephalopathy and successfully underwent liver transplantation with resolution of his symptoms post-transplant. DISCUSSION: This case demonstrates the importance of early evaluation, diagnosis and management of acute liver in patients with indication of DRESS Syndrome. It also emphasizes the importance of early transfer of patients with significant liver involvement to a liver transplant center as it can improve clinical outcomes.