Abstract: Albumin dialysis by the molecular adsorbents recirculating system (MARS) and by fractionated plasma separation, adsorption, and dialysis (Prometheus[PROM]) represent novel nonbiological liver support systems specifically designed to remove albumin-bound substances. Preliminary evidence suggests a favorable impact of MARS on the course and outcome of liver failure. This study aimed at comparing the detoxification capacity of both devices. For this purpose, we performed a retrospective analysis on data prospectively collected in patients with acute-on-chronic liver failure treated with either the MARS (n = 9) or the PROM (n = 9) device on 2–5 consecutive days. Each treatment was performed for at least 5 h at identical blood and dialysate flows. Blood clearances were calculated during the first treatment session for urea nitrogen, creatinine, total bilirubin, and bile acids from paired arterial and venous line samples after 1, 4, and 6 h of treatment. Reduction ratios for all single-treatment sessions, and the overall treatment phase, were calculated from pretreatment and post-treatment values. For all markers but bile acids, the single-treatment as well as the overall treatment phase reduction ratios obtained with PROM were significantly higher compared with those obtained with MARS. PROM led at all time points to higher clearances for all evaluated solutes. Blood clearances of protein-bound substances declined over time with MARS, but not with PROM. In conclusion, a significant decline in the serum level of water-soluble and protein-bound toxins was achieved with both devices. PROM produces higher blood clearances for most toxins, which results in higher delivered treatment doses compared with a matching treatment with MARS.