BACKGROUND AND AIMS: Refractory ascites (RA) is a severe, graft-threatening complication associated with decompensated liver cirrhosis (LC), and new and efficient therapeutic strategies for RA are urgently needed. Due to the anti-fibrotic and regenerative properties, mesenchymal stem cells (MSCs) could be an interesting candidate. This study assessed the safety and efficacy of human autologous bone marrow-derived MSCs (ABM-MSCs) infusions in patients with decompensated LC and RA. METHODS: From January 2012 to June 2014, 39 chronic hepatitis B patients with decompensated LC and RA were recruited as the MSCs group in this phase I, prospective, and single-center clinical study. Patients in this group received a single dose of ABM-MSCs (about 1.0×106/kg MSCs through hepatic artery infusion) and the standard medical treatment (SMT). The SMT was applied during February 2012 to December 2014 in 39 HBV-related decompensated LC patients with RA patients who were treated as the control group. Liver function, the need for paracenteses, survival, and the development of other related complications were evaluated for the therapeutic efficacy of MSCs treatment. Adverse events were monitored up to 2 years after MSCs infusions. RESULTS：No significant side-effects and severe complications were observed in either group. Compared with the baseline, the levels of serum albumin and prothrombin time were increased, and the level of serum total bilirubin was decreased after ABM-MSCs infusions at week 48 (P <0.05). ABM-MSCs therapy also decreased the Model for End-Stage Liver Disease scores compared with that in the control group (14.41±3.39 vs 16.50±3.17, p=0.006). The 2-year survival rates were higher in the ABM-MSCs group than in the control group (97% and 85%, p=0.49). The rate of disappearance of the hypogastric ascites volume is prominently higher in the ABM-MSCs group than in the control group (23% and 5%, p=0.047).The percentages of patients who developed hepatorenal syndrome, hepatic encephalopathy, or primary peritonitis were lower in the ABM-MSCs group than in the control group (3% vs 15%, 5% vs 13%, and 8% vs 15%). CONCLUSION: The ABM-MSCs infusions are clinically safe and favorable when used in a short-term treatment. For these reasons, infusions may become a novel treatment for patients with HBV-related decompensated liver cirrhosis with refractory ascites. (Am J Transl Med 2020. 4:122-139).