Abstract: Extracorporeal liver devices have gained great attention as a complementary approach to liver transplantation in patients with acute on chronic liver failure. Among others, Molecular Adsorbent Recycling System (MARS) is a hemodiafiltration against albumin able to remove low molecular weight toxins. We aimed to validate the use of MARS in patients presenting with acute on chronic liver failure with severe cholestasis. We enrolled 7 patients with acute on chronic liver failure, presenting with bilirubin >25 mg/dl and hepatorenal syndrome and/or hepatic encephalopathy grade >II. Liver biochemistry, coagulation, blood cell count, electrolytes, ammonia, lactate, blood urea nitrogen, creatinine, bile acids, Fischer ratio, and encephalopathy grade were assessed before and after each MARS treatment. MARS can represent a safe therapeutic choice to achieve a quick improvement of neurological status, a hemodynamic stability, and a better clinical outcome. In particular, our encouraging results suggest that also, patients with severe cholestasis may represent in the future a good indication for MARS treatment.