Ski-interacting protein (SKIP) is a transcriptional cofactor distinct from other cofactors and involved in the regulation of many cancer-related proteins. This study investigated the expression of SKIP and its potential clinical and biological significances in hepatocellular carcinoma (HCC). Immunohistochemistry and Western blot were performed to detect the expression of SKIP in clinical HCC samples and adjacent noncancerous tissues. In addition, expression of SKIP was correlated with clinicopathological variables, and univariate and multivariate survival analyses were performed to determine the prognostic significance. Moreover, the biological significance of the aberrant expression of SKIP was investigated in vitro. High SKIP expression was detected in clinical HCC samples compared with adjacent noncancerous tissues. Expression of SKIP correlated directly with the histological grades of HCC and high expression of SKIP was associated with a poor prognosis. SKIP depletion by small interfering RNA inhibited cell proliferation and blocked S phase entry in HepG2 cells. Owing to overexpression of SKIP in HCC tissues and its important role in predicting poor prognosis and the development of HCC, SKIP could be a potential prognostic marker and therapeutic target of HCC.