Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation of chronic liver disease associated with organ failures. Anemia of diverse etiology is common in patients with ACLF. Spur cell anemia (SCA) is a form of acquired hemolytic anemia that occurs rarely in such patients due to dysregulated lipids metabolism. Spur cells are large erythrocytes with spike-like projections, which predispose them for sequestration and destruction in splenic canaliculi. There is a paucity of data on SCA in patients with ACLF. Here we report a series of five ACLF patients who had severe (hemoglobin level < 8 g/dL) and transfusion-refractory SCA with aggressive clinical course and high mortality rate.