Introduction: Primary myelofibrosis (PMF) is a chronic myeloproliferative disorder most commonly seen in older adults which can lead to liver and spleen involvement due to extramedullary hematopoiesis (EMH). High RBC turnover can lead to hyperbilirubinemia. We describe an unusual case of cholestatic liver injury in a patient with PMF, with otherwise unremarkable workup with a notable response to ruxolitinib. There are no other similar reported cases in the literature. Case Description/Methods: A 64 year old male with a 10-year history of asymptomatic PMF under observation presented with pruritus and jaundice for 3 days. Labs: ALT 49 IU/L, AST 35 IU/L, ALP 378 IU/L, total bilirubin (TB) 17 mg/dL and direct bilirubin 10 mg/dL. Workup for metabolic, viral, autoimmune, alcoholic, and drug-induced liver disease was unrevealing. CT scan showed hepatomegaly, portal vein enlargement, and splenomegaly. MRCP, EUS, and ERCP were unremarkable. Liver biopsy revealed cholestatic liver injury. TB increased to 25 mg/dL, and repeat ERCP failed to show biliary obstruction. Repeat liver biopsy showed similar findings. TB rose to 29 mg/dL, and given negative workup, he was empirically treated for possible PMF related disease. Ruxolitinib was initiated with improvement of TB to 18 mg/dL. 3 weeks after initiation, Ruxolitinib was held due to adverse effects, and TB increased to 35 mg/dL over the next 5 weeks. Ruxolitinib was resumed at lower dose with improvement again of TB to 24 mg/dL. Patient’s course was complicated by biopsy-confirmed bile-acid nephropathy, ascites, functional decline and eventually was transitioned to hospice. Discussion: Our case highlights hyperbilirubinemia as a rare manifestation of PMF. A hallmark of PMF is progressive bone marrow fibrosis and ineffective erythropoiesis, which leads to myeloid metaplasia and EMH often involving the liver and spleen. This can lead to hepatosplenomegaly, abnormal liver function tests, and portal hypertension. Diagnosis is often made by liver biopsy demonstrating EMH. Although we entertained the possibility of EMH, our patient had negative workup including 2 liver biopsies and we unfortunately could not reach a definitive diagnosis. Given the temporal relationship between myelofibrosis treatment and TB improvement, we speculate EMH was likely the underlying etiology of his cholestatic liver injury. EMH should be considered for patients with PMF presenting with hyperbilirubinemia.Figure 1.: A. H&E stain (200x) showing marked canalicular cholestasis, bile duct injury and ductular reaction with portal and lobular neutrophilic infiltrates. B. Graph illustrating the total bilirubin trend in response to initiation and discontinuation of Ruxolitinib.