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Objective To investigate the efficacy of hematopoietic stem cell (HSC) transplantation via the hepatic artery vs. the portal vein for end-stage liver disease (ESLD). Methods Patients with hepatic decompensation were prospectively recruited from September 2010 to September 2012 to receive HSC transplantation via the hepatic artery or the portal vein. Liver function was examined at 3, 6, and 12 months after transplantation. Liver biopsy results were analyzed using the Knodell score. Results Eighty patients (58 males and 22 females) were enrolled in the study. The Child-Pugh score was grade B in 69 cases, and grade C in the remaining 11 cases. HSC transplantation was performed via the portal vein in 36 patients and via the hepatic artery in 44 patients. ALT levels decreased while serum albumin levels increased significantly in both groups at 6 and 12 months after HSC transplantation (P