Background: Viral hepatitis, drug abuse and metabolic diseases cause liver injury. Stem cell conditioned media (CM) alone can offer organ repair as compared to stem cell therapy. Objective: This study was designed to investigate role of bone marrow derived mesenchymal stem cells (BM-MSCs) CM in comparison to BM-MSCs in amelioration of liver injury in carbon tetrachloride (CCl4) induced liver fibrosis Materials and Methods: PKH26 -labeled MSCs were transplanted into one albino rats group with CCl4 induced liver fibrosis. MSCs-CM was injected in another group. Hematoxylin and eosin staining, Masson trichrome for collagen, Periodic Acid Schiff for glycogen, immunohistochemical and biochemical analysis were done to compare the morphological and functional liver regeneration among groups. The expression differences of CYP7A1, CYP27A1, glutathione reductase, glutathione peroxidase, albumin and interleukins were examined by real-time polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA). Results: MSCs and CM transplantation significantly increased antioxidant enzymes activity in injured liver. Also, gene expression levels attenuated by CCl4, were increased up to basal levels. CCl4 group showed different degrees of pathology with some severely affected lobules. MSCs group showed nearly normal organization apart from some dilated sinusoids and vacuolated cells. MSCs-CM injection revealed almost normalized liver histological and immunohistochemical picture. Conclusion: BM-MSCs conditioned medium is found to play a predominant therapeutic role in chronic liver fibrosis as compared to BM-MSCs.