Introduction: Nafcillin induced acute liver injury is a rare and potentially fatal complication that has been known since the 1960s but inadequately studied. At this time, the only proven treatment is early discontinuation of the drug. Because of the high prevalence of nafcillin class antibiotic use in the United States, it is important for clinicians to have a high clinical suspicion for this diagnosis. Our case highlights the importance of early detection and recognition of the signs and symptoms early in the disease course. Case Presentation: A 68-year old male with a history methicillin-sensitive staphylococcus and L3/L4 osteomyelitis on antibiotic therapy presented with painless jaundice after starting intravenous nafcillin therapy. Prior to starting the medication, the patient had liver enzymes within normal limits and normal bilirubin levels. At the time of presentation, the patient's lab work exhibited a bilirubin/direct bilirubin of 9.4/8.2 mg/dL; alkaline phosphatase of 311 IU/L; AST/ALT of 109/127 IU/L. The patient was switched to IV vancomycin given concern for drug-induced liver injury. Imaging did not show obstruction of the hepatobiliary or pancreaticobiliary trees. Serology was unremarkable for viral etiology, autoimmune processes, Wilsons disease, and hemochromatosis. A liver biopsy showed findings consistent with drug-induced liver injury. The patient's liver function tests peaked at day seven of admission and trended towards normal levels with cessation of nafcillin therapy. The patient was discharged with a diagnosis of nafcillin induced acute liver injury. Discussion: Nafcillin-induced liver injury is a rare process that is associated with high levels of morbidity and mortality. We present a case of liver failure attributable to nafcillin use that necessitated discontinuation of the drug. Our case highlights the importance of early recognition of the diagnosis and careful monitoring of liver function when nafcillin is employed in the clinical setting.