Cystine/glutamic acid transporter (xCT) plays a role in tumor progression by regulating the redox status in several types of cancers. To demonstrate the importance of xCT expression for predicting the prognosis of hepatocellular carcinoma (HCC), we analyzed xCT gene expression in 130 paired HCC and non-cancerous tissues. xCT protein expression was confirmed using 7 HCC cell lines and samples from human subjects. xCT mRNA expression was detected in 34 (26%) tumor tissues. Expression of xCT was higher in HCC tissues compared to the corresponding normal tissues according to quantitative reverse transcriptase-polymerase chain reaction findings (P< 0.0001). Patients in the group presenting with xCT mRNA expression showed poorer overall and disease-free survival than did those with an absence of xCT mRNA (P= 0.0130 and 0.0416, respectively). xCT mRNA expression proved to be an independent factor for poor prognosis in a multivariate analysis of overall survival (hazard ratio, 1.68; 95% CI, 1.03-2.92). We observed xCT protein expression in both the HCC cell lines and in human tissue samples. In conclusion, the findings of the present study suggest that xCT is useful as a predictive marker for patient prognosis and that it may be a novel therapeutic target for HCC.