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Interleukin (IL)-10 is a pleiotropic cytokine with anti-inflammatory and immunosuppressive properties in liver failure. Biomarkers are urgently needed to predict prognosis of acute-on-chronic hepatitis B liver failure (ACHBLF).To investigate the potential diagnostic value of plasma IL-10 as a biomarker for predicting the mortality of ACHBLF.This prospective study consisted of 115 newly diagnosed ACHBLF patients from May 2009 to October 2013 as a training cohort and 54 ACHBLF patients from November 2013 to March 2015 as a validating cohort. Plasma IL-10 level was measured using enzyme-linked immunosorbent assay.In the training cohort, the plasma IL-10 level of nonsurvivals [median (centile25; centile75): 12.38 (8.76; 15.52) pg/mL] was significantly higher than that in survivals [6.55 (5.43; 7.65) pg/mL, P < 0.001]. Plasma IL-10 (hazard ratio = 1.205, 95% confidence interval: 1.145–1.267, P < 0.001) was identified as an independent risk factor for mortality of ACHBLF patients. Furthermore, plasma IL-10 showed higher area under the curve of receiver operating characteristic (AUROC) than model for end-stage liver diseases (MELD) for predicting 1-month (0.887 vs. 0.779, P < 0.05), 2-month (0.878 vs. 0.779, P < 0.05) and 3-month (0.917 vs. 0.776, P < 0.001) mortality. However, we did not find significant differences in AUROC between IL-10 and IL-10 plus MELD for 1-, 2- and 3-month mortality. ACHBLF patients with plasma IL-10 > 9.6 pg/mL showed poor survival time than patients with plasma IL-10 ≤ 9.6 pg/mL at the end of 1 month in the training and validation cohorts.Plasma IL-10 performed better than MELD in predicting the prognosis of acute-on-chronic hepatitis B liver failure. Furthermore, plasma IL-10 > 9.6 pg/mL predicts a poor 1-month mortality.