Abstract: Liver cirrhosis represents the final pathway of all chronic hepatic injury. Replacement the damaged hepatocytes through cell-based therapies have been a promising therapeutic agent for tissue regeneration. This study aimed to assess the effect of treatment with Hepatocyte Differentiated Mesenchymal Stem Cells (HD-MSCs) in experimentally induced canine liver cirrhosis. Experimental induction of liver cirrhosis was done on 18 skeletally mature mongrel dogs using carbon tetrachloride (CCl4) for 16 weeks; dogs were evaluated for cirrhosis through clinical, Liver Function Tests (LFTs), ultrasonography with Portal Vein (PV) and Hepatic Vein (HV) diameter estimation and histopathological examination. Dogs were randomly allocated into one of the two study groups; Sham group: CCl4 with no HD-MSCs treatment and group II: CCl4 with HD-MSCs treatment then dogs were evaluated for the efficacy of cell treatment through clinical, LFTs, ultrasonography with PV and HV diameter estimation, postmortem examination, histopathological examination of liver tissue and relative quantitative expression of collagen Iα and albumin were measured by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). The HD-MSCs administration restored liver function that was confirmed by clinical, LFTs, histopathology and RT-PCR. Liver tissue ultrasonography, PV and HV diameter were improved. The study proves the ability of HD-MSCs to potentially improve cases of liver cirrhosis.