Introduction: Fluoxetine is a commonly prescribed antidepressant with generalized gastrointestinal side effects that can include nausea and diarrhea. While fluoxetine is metabolized in the liver, fewer than 1% of patients develop a mild and self-limited transaminitis. Here, we present a unique case of clinically apparent drug-induced liver injury (DILI) soon after fluoxetine initiation. Case Description/Methods: A 28-year-old male with schizophrenia and bipolar disorder was admitted to the hospital due to a 3-day history of worsening right upper quadrant (RUQ) abdominal pain with a 2day history of yellowing of the skin and eyes. A thorough history revealed that he was on chronic citalopram and olanzapine therapy but was started fluoxetine (20 mg daily) 5-days prior. Additionally, he denied use of alcohol, recreational drugs, and herbal supplements, and denied a history of known liver disease. On admission, the patient was alert and oriented x4 with jaundice, scleral icterus, and asterixis. Laboratory work demonstrated WBC 15,000, platelets 235,000, ammonia 131, AST 3219, ALT 6574, ALP 181, total bilirubin 22.9, and INR 1.97. Acetaminophen and salicylate levels were unremarkable. Fluoxetine was held immediately, and the patient was empirically given N-acetylcysteine. RUQ ultrasound was unremarkable. MRCP demonstrated fatty infiltration of the liver without nodularity or biliary dilation. A thorough workup including viral hepatitis (A, B, C, E), EBV, CMV, HIV, hemochromatosis, Wilson's disease, and autoimmune hepatitis was unremarkable. A liver biopsy was performed, and pathology was consistent with mixed-pattern DILI. With the removal of fluoxetine, the patient's liver function tests and clinical symptoms continued to improve, and on hospital day 10 he was discharged in stable condition. Discussion: Transaminitis from fluoxetine is typically mild, asymptomatic, and self-limited. Our case highlights a rare instance where fluoxetine precipitated DILI. It is unclear whether polypharmacy with his other psychiatric medications, or underlying hepatic steatosis, were predisposing factors to developing fluoxetine-associated DILI. Higher awareness of fluoxetine-associated hepatotoxicity is needed and caution should be used when considering current medications and underlying liver pathology when starting this medication.