Hepatocellular carcinoma (HCC) represents the fifth and ninth cause of mortality among male and female cancer patients, respectively and typically arises on a background of a cirrhotic liver. HCC develops in a multi-step process, often encompassing chronic liver injury, steatosis and cirrhosis eventually leading to the malignant transformation of hepatocytes. Aberrant expression of the class I homeobox gene family (HOX), a group of genes crucial in embryogenesis, has been reported in a variety of malignancies including solid tumors. Among HOX genes, HOXA13 is most overexpressed in HCC and is known to be directly regulated by the long non-coding RNA HOTTIP. In this study, taking advantage of a tissue microarray containing 305 tissue specimens, we found that HOXA13 protein expression increased monotonically from normal liver to cirrhotic liver to HCC and that HOXA13-positive HCCs were preferentially poorly differentiated and had fewer E-cadherin-positive cells. In two independent cohorts, patients with HOXA13-positive HCC had worse overall survival than those with HOXA13-negative HCC. Using HOXA13 immunohistochemistry and HOTTIP RNA in situ hybridization on consecutive sections of 16 resected HCCs, we demonstrated that HOXA13 and HOTTIP were expressed in the same neoplastic hepatocyte populations. Stable overexpression of HOXA13 in liver cancer cell lines resulted in increased colony formation on soft agar and migration potential as well as reduced sensitivity to sorafenib in vitro. Our results provide compelling evidence of a role for HOXA13 in HCC development and highlight for the first time its ability to modulate response to sorafenib.