Objectives: The C-reactive protein-to-albumin ratio (CAR) is a prognostic marker in various diseases that represents patients’ inflammation and nutritional status. We aimed to investigate the prognostic value of CAR in critically ill patients with severe acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT). Methods: We retrospectively collected data from eight tertiary hospitals in Korea from 20062021. The patients were divided into quartiles according to CAR levels at the time of CRRT initiation. The primary outcome was the in-hospital mortality rate. The secondary outcomes were the 7- and 30-day mortality.Cox regression analyses were performed to investigate the effect of CAR on in-hospital mortality. The mortality prediction performance of CAR was evaluated using the area under the curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results: In total, 3995 patients who underwent CRRT were included, and the in-hospital mortality rate was 67.3% during the follow-up period. The 7-day, 30-day, and in-hospital mortality rates increased toward higher CAR quartiles (all P<0.001). After adjusting for confounding variables, the higher quartile groups had an increased risk of in-hospital mortality (quartile 3: adjusted hazard ratio [aHR], 1.15, 95% confidence interval [CI], 1.021.30, P=0.023; quartile 4: aHR, 1.33; 95% CI, 1.181.50, P<0.001). Combination of CAR with Assessment and Chronic Health Evaluation II (APACHE II) or Sequential Organ Failure Assessment (SOFA)scores significantly increased predictive power than that of each severity score alone in AUC, NRI and IDI (all P<0.05). Conclusions: A high CAR is associated with increased in-hospital mortality in critically ill patients requiring CRRT. The combined use of CAR and severity scores provides better predictive performance for mortality than the severity score alone.