OBJECTIVES: Hyperammonemia is a key contributing factor for cerebral edema in acute liver failure. Continuous renal replacement therapy may help reduce ammonia levels. However, the optimal timing, mode, intensity, and duration of continuous renal replacement therapy in this setting are unknown. We aimed to study continuous renal replacement therapy use in acute liver failure patients and to assess its impact on hyperammonemia. DESIGN: Retrospective observational study. SETTING: ICU within a specialized liver transplant hospital. PATIENTS: Fifty-four patients with acute liver failure. INTERVENTIONS: Data were obtained from medical records and analyzed for patient characteristics, continuous renal replacement therapy use, ammonia dynamics, and outcomes. MAIN RESULTS: Forty-five patients (83%) had high grade encephalopathy. Median time to continuous renal replacement therapy commencement was 4 hours (interquartile range, 2-4.5) with 35 (78%) treated with continuous venovenous hemodiafiltration and 10 (22%) with continuous venovenous hemofiltration. Median hourly effluent flow rate was 43 mL/kg (interquartile range, 37-62). The median ammonia concentration decreased every day during treatment from 151 µmol/L (interquartile range, 110-204) to 107 µmol/L (interquartile range, 84-133) on day 2, 75 µmol/L (interquartile range, 63-95) on day 3, and 52 µmol/L (interquartile range, 42-70) (p < 0.0001) on day 5. The number of patients with an ammonia level greater than 150 µmol/L decreased on the same days from 26, to nine, then two, and finally none. Reductions in ammonia levels correlated best with the cumulative duration of therapy hours (p = 0.03), rather than hourly treatment intensity. CONCLUSIONS: Continuous renal replacement therapy is associated with reduced ammonia concentrations in acute liver failure patients. This effect is related to greater cumulative dose. These findings suggest that continuous renal replacement therapy initiated early and continued or longer may represent a useful approach to hyperammonemia control in acute liver failure patients.