Patients with liver failure may suffer citrate accumulation when using regional citrate anticoagulation for artificial liver support system therapy (RCA-ALSS therapy). This study aimed to develop a predictive scoring system to stratify the risk of citrate accumulation. A total of 338 patients treated with RCA-ALSS therapy were retrospectively enrolled and randomly divided into derivation and validation cohorts. Longer duration of citrate accumulation (LDCA) was defined as the presence of citrate accumulation 2 h after RCA-ALSS therapy. Four baseline variables were found to be independently associated with LDCA: gender, international normalized ratio of prothrombin time, serum creatinine, and serum chloride. A predictive R-CA model and its simplified R-CA score were developed. The R-CA model (AUROC = 0.848) was found to be superior to the MELD score (AUROC = 0.725; p = 0.022) and other univariate predictors (AUROCs < 0.700; all p ≤ 0.001) in predicting LDCA. The R-CA score (AUROC = 0.803) was as capable as the R-CA model (p = 0.369) and the MELD score (p = 0.174), and was superior to other univariate predictors (all p < 0.05) in predicting LDCA. An R-CA score of 0-2 had a negative predictive value of 90.2% for LDCA. Our R-CA score reliably predicts LDCA in patients with RCA-ALSS therapy, and it is easy to use. Patients with R-CA score of 0-2 can safely receive RCA-ALSS therapy, while others should be carefully evaluated before treatment. Trial registration: Chinese Clinical Trial Registry, ChiCTR2000029179. Registered 17 January 2020, https ://www.chict r.org.cn/showp roj.aspx?proj=48084. Acute-on-chronic liver failure (ACLF) is a progressive disease associated with rapid clinical deterioration and high mortality. Artificial liver support system (ALSS) therapy is an available treatment for patients with ACLF and is a bridge to liver transplantation 1. However, the optimal extracorporeal anticoagulation regimen for ALSS therapy remains uncertain. Regional citrate anticoagulation (RCA) is now the preferred anticoagulation method for patients underwent continuous renal replacement therapy (CRRT) 2,3. RCA seems also safe and feasible for patients with liver failure, and citrate accumulation is well tolerated by them 4-14. The blood purification techniques used in these patients include a dialysis technique that can remove citrate directly. Our previous study suggests that RCA is relatively safe and effective in patients with ACLF receiving double plasma molecular adsorption system plus plasma exchange (DPMAS plus PE) therapy that does not include dialysis and filtration techniques 15. However, transient citrate accumulation was found in all patients due to PE therapy in both groups and RCA in RCA group, and it remained much higher in RCA group than that in heparin anticoagulation group 2 h after the conclusion of the ALSS therapy (34.0% vs. 7.4%, p = 0.000) 15. Citrate accumulation is a feared and potentially lethal complication of RCA manifesting as an increased ratio of total calcium (Ca tot) to ionized calcium (Ca ...