The pathophysiological basis of acute-on-chronic liver failure (ACLF) is unclear but systemic inflammatory response is thought to be important. In patients with ACLF, the molecular adsorbents recirculating system (MARS) improves individual organ function, but the effect of MARS on the proposed mediators of systemic inflammatory response is unclear. The present study was designed to determine the effect of MARS on the cytokine profile, oxidative stress, nitric oxide, and ammonia. A total of 18 patients with alcohol-related ACLF due to inflammation-related precipitants were randomized to receive standard medical therapy (SMT) alone, or with MARS therapy over 7 days. Plasma cytokines, malondialdehyde (MDA), free radical production, nitrate / nitrite (NOx), and ammonia were measured. Encephalopathy improved significantly with MARS (P < .01), but not with SMT. Mean arterial pressure and renal function remained unchanged. No significant change of plasma cytokines and ammonia levels were observed in either group. Plasma MDA levels did not change either. There was a fall in NOx (P < .05) with MARS, but not with SMT. In conclusion, in inflammation-related ACLF patients, albumin dialysis using MARS results in improvement of encephalopathy, independent of changes of ammonia or cytokines, without improving blood pressure or renal function. These results should temper the liberal use of MARS until further data is available.