Background: End-stage liver disease (ESLD) is the final stage of a liver disease, which is characterized by liver cirrhosis. ESLD largely increases possibility of liver cancers in the world. The stem cell transplantation has become an emerging therapy to treat various liver diseases including ESLD, while whether it causes liver cancer remains unclear. The study aims to analysis the long-term therapeutic effect of umbilical cord blood-derived mesenchymal stem cells (UC-MSCs) transplantation in ESLD patients. Patients and Methods: 50 ELSD patients of non-UC-MSCs transplantation and 45 ELSD patients of UC-MSCs transplantation were retrospectively analyzed. The clinical outcomes in clinical and biochemical data, complications, and quality of life were recorded at 3, 6, 12, 36, and 60 months. Results: It was found that the incidence of liver cancer was much lower in ESLD patients with UC-MSCs transplantation than in ESLD patients without UC-MSCs transplantation (12% VS 2.2%). The survival percentage was improved by treatment with UC-MSCs transplantation compared with non-UC-MSCs transplantation in ESLD patients during the five years follow-up. The inflammation and fibrosis scores were decreased in the ESLD patients with UC-MSCs transplantation. The liver cirrhosis was largely improved, and Child-Pugh scores were decreased. Conclusions: UC-MSCs transplantation is able to decrease the risks of liver cancers in ELSD patients. The reduction of liver cancer incidence might be related to decrease of inflammation by UC-MSCs transplantation. More efforts should be investigated towards increasing the number of patients and follow-up time to further verify the therapeutic benefits of UC-MSCs translations in treating liver cancers.