Herein, we observed high expression of Shp2 in both chemoresistant hepatocellular carcinomas (HCCs) and recurrent HCCs from patients. A remarkable increase of Shp2 was detected in sorted epithelial cell adhesion molecule–positive or cluster of differentiation 133–positive liver CSCs and in CSC-enriched hepatoma spheroids from patients. Up-regulated Shp2 facilitated liver CSC expansion by promoting the dedifferentiation of hepatoma cells and enhancing the self-renewal of liver CSCs. Mechanistically, Shp2 dephosphorylated cell division cycle 73 in the cytosol of hepatoma cells, and the dephosphorylated cell division cycle 73 bound β-catenin and facilitated the nuclear translocation of β-catenin, which promoted the dedifferentiation of hepatoma cells. Shp2 increased β-catenin accumulation by inhibiting glycogen synthase kinase 3β–mediated β-catenin degradation in liver CSCs, thereby enhancing the self-renewal of liver CSCs. Blockage of β-catenin abolished the discrepancy in liver CSC proportion and the self-renewal capacity between Shp2-depleted hepatoma cells and control cells, which further confirmed that β-catenin is required in Shp2-promoted liver CSC expansion. More importantly, HCC patients with low Shp2 levels benefited from transcatheter arterial chemoembolization or sorafenib treatment, but patients with high Shp2 expression did not, indicating the significance of Shp2 in personalized HCC therapy. Conclusion: Shp2 could promote HCC cell dedifferentiation and liver CSC expansion by amplifying β-catenin signaling and may be useful in predicting patient response to chemotherapeutics. (Hepatology 2017;65:1566-1580).