HGF is a potent agent for acceleration of tissue regeneration following an acute insult, VEGF plays an important role in liver regeneration and this may be due to its effects on neovascularization. The aim of this study was to prove the role of HGF/VEGF gene transfer in enhancing proliferation of remnant liver following experimental 80% of portal vein ligation. Methodology: 6 adult Mongrel dogs divided into three groups control group: received PBS. lac-Z group : received Ad-CMV-Lac Z. HGF/VEGF group: received both Ad-CMV-HGF gene & Ad-CMV-VEGF gene. 80% portal vein ligation was done on the third day, Blood samples were obtained periodically (days 1, 3, 4, 5, 7, 9) for liver function, CBC, HGF, VEGF & TNF. PCR was done on different tissues to detect E4 region of the virus and RT- PCR for analysis of HGF& VEGF gene expression. The results showed that the virus incorporated into the liver tissue only and not in other tissues such as kidneys, spleen, lungs, heart and retina. High levels of expression were obtained on the 3rd day after injection of the virus and declined thereafter. HGF mRNA and VEGF mRNA were expressed on liver tissues only on day 3 and diminished thereafter. Plasma HGF and VEGF proteins concentration was not increased in the VEGF/HGF group compared with that of the control and Lac-Z group. Expression of PCNA was detected at day 3. It showed few positively stained nuclei with labeling index 5 in lac-Z group and abundant positively stained binucleated hepatocytes (rounded nuclei) and nonparenchymal cells (flat nuclei) with labeling index 25 in HGF/VEGF group. Conclusions: HGF and/or VEGF gene transfer effectively promoted liver regeneration after portal vein ligation with increased proliferation of both hepatocytes and SECs and without systemic elevation of HGF and VEGF.