Abstract: Aim: Recent studies have implicated aberrant Notch signaling in human hepatocellular carcinoma (HCC). Yet, relatively little is known about the role of wild type Notch signaling in human hepatocarcinogenesis. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. Notch-Ras cooperation promotes hepatic cells carcinogenesis is not documented yet. Methods: The correlations and biological effects of Notch1 and Ras were analyzed introducing recombinant vectors NICD-pEGFP-C1 and/or H-Ras-pEGFP-C1 to human non-tumor hepatic cell line L02 cells. The viability of L02 cells transfected with recombinant vector was performed by MTT and the proliferation of L02 cells was tested using clone assay. The transformation of L02 cells was evaluated in vivo. Results: MTT assay showed that forced overexpression of Notch1-ICD and H-Ras promotes proliferation and growth than unmanipulated L02 cells (P<0.01). Cells treated with DAPT showed a significant reduction in cell viability compared with controls (P<0.01). Constitutively active Notch1 alone failed to transform immortalized L02 cells in vivo, it synergized with the Ras pathway to promote hepatic cells transformation (P<0.01). Conclusions: We showed that Ras-Notch signaling cooperation drives hepatic cells transformation and stimulates proliferation. Dysregulated Notch signaling cooperation with the Ras in transformation and proliferation offers combined inhibition of the two pathways as an attractive avenue for therapeutic intervention for this advanced disease. Key words Notch signaling, Ras, transformation, proliferation, hepatocarcinogenesis Abbreviation: H-Ras-pEGFP-C1, H-Ras; NICD-pEGFP-C1, NICD; N-(N-[3,5-difluorophenacetyl]-L-alanyl)-Sphenylglycine t-butyl ester, DAPT