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Primary hepatic carcinoma (PHC) is a leading threat to cancer patients with few effective treatment strategies. OPN is found to be an oncogene in hepatocellular carcinoma (HCC) with potential as a treating target for PHC. Fenofibrate is a lipid-lowering drug with potential anti-tumor properties, which is claimed with suppressive effects on OPN expression. Our study proposes to explore the molecular mechanism of fenofibrate in inhibiting HCC. OPN was found extremely upregulated in 6 HCC cell lines, especially Hep3B cells. Hep3B and Huh7 cells were treated with 75 and 100 μM fenofibrate, while OPN-overexpressed Hep3B cells were treated with 100 μM fenofibrate. Decreased clone number, elevated apoptotic rate, reduced number of migrated cells, and shortened migration distance were observed in fenofibrate-treated Hep3B and Huh7 cells, which were markedly abolished by the overexpression of OPN. Furthermore, the facilitating effect against apoptosis and the inhibitory effect against migration of fenofibrate in Hep3B cells were abolished by 740 Y-P, an agonist of PI3K. Hep3B xenograft model was established, followed by treated with 100 mg/kg and 200 mg/kg fenofibrate, while OPN-overexpressed Hep3B xenograft was treated with 200 mg/kg fenofibrate. The tumor growth was repressed by fenofibrate, which was notably abolished by OPN overexpression. Furthermore, the inhibitory effect of fenofibrate on the PI3K/AKT/Twist pathway in Hep3B cells and Hep3B xenograft model was abrogated by OPN overexpression. Collectively, fenofibrate suppressed progression of hepatoma downregulating OPN through inhibiting the PI3K/AKT/Twist pathway. [ABSTRACT FROM AUTHOR]