Considering the association between the overexpression of HNF4a and reduction in cancerous phenotype of HCC cells, in the present study through a differentiation therapy approach, we investigated the effect of HNF4a induced expression in HCC cell lines after treatment with CLA, the natural ligand of HNF4a. Hep-3B as primary and Sk-Hep-1 as stromal liver cancer cell lines were assessed to show whether CLA treatment can reduce various cancerous features including proliferation rate, colony formation, and migration capacity. This evidence concerns the gene HNF4A and hepatocellular carcinoma.