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Abstract: Background and Aim: The aim of our study was to investigate the immunomodulatory effect and short‐term efficacy and long‐term prognosis of decompensated liver cirrhosis patients caused by hepatitis B after a double transplantation with human umbilical cord mesenchymal stem cells (hUCMSCs). Methods: Fifty inpatients were recruited and given the same medical treatments, receiving hUCMSCs injection intravenously. Fifty‐three patients (Group B) matched for age, sex, and baseline alanine aminotransferase, aspartate aminotransferase, albumin, total bilirubin, prothrombin time, and model for end‐stage liver disease score and Child–Pugh classification, acted as the control group. Results: Interleukin‐6 and tumor necrosis factor alpha levels markedly decreased, and interleukin‐10 level apparently increased in Group A at 2 and 4 weeks after treatment. Transforming growth factor beta in Group A increased more remarkably at 2 weeks after treatment. T4 cells and Treg cells in Group A were apparently higher than those in Group B at 2 and 4 weeks after treatment, and T8 cells and B cells were significantly lower than those in Group B. Aspartate aminotransferase levels in Group A were dramatically declining at 8 and 12 weeks after treatment. Levels of albumin, total bilirubin, and prothrombin time in Group A were apparently improved from 4 to 12 weeks after treatment. The improvements in model for end‐stage liver disease and Child–Pugh scores in Group A were notably superior to those in Group B from 4 to 36 weeks after treatment. There were no remarkable differences in the incidence of developing liver failure throughout the follow‐up period, but the mortality rate of Group A was lower than that of Group B. Conclusion: This therapeutic method may be an appropriate choice for patients with decompensated liver cirrhosis. [ABSTRACT FROM AUTHOR]