The Y-Box-binding protein-1, a member of the cold-shock domain DNA- and RNA-binding protein superfamily, is known to mediate chemoresistance. The aim of this study was to determine the expression of Y-Box-binding protein-1 in nasopharyngeal cancer in vitro and in tumor tissue samples as well as analyze the clinicopathological significance of Y-Box-binding protein-1 expression in nasopharyngeal cancer, in particular as a predictor of outcome after treatment. The Y-Box-binding protein-1 expression profile was evaluated at the mRNA and protein levels in poorly differentiated CNE-2 nasopharyngeal cancer cells by real-time RT-PCR, western blot analysis and immunohistochemistry. Y-Box-binding protein-1 expression in 143 nasopharyngeal cancer specimens was examined by immunohistochemistry and correlated with clinicopathologic parameters. Y-Box-binding protein-1 mRNA and protein were found to be expressed in CNE-2 nasopharyngeal cancer cells in vitro. Of 143 patient tissue sections, 137 (96%) were stained positive for the Y-Box-binding protein-1 protein. Y-Box-binding protein-1 immunostaining was observed to be predominantly cytoplasmic. A higher recurrence of nasopharyngeal cancer was found in patients whose tissues had increased Y-Box-binding protein-1 expression (P<0.001). The Cox proportionate hazard regression model also established that high Y-Box-binding protein-1 immunoreactivity was significantly correlated with increased risk (2.13 times) of recurrence as compared to low Y-Box-binding protein-1 immunoreactivity (P=0.01). Within groups of patients treated by radiotherapy or chemoradiotherapy, recurrent cases had significantly higher Y-Box-binding protein-1 expression than nonrecurrent cases (P<0.001 and P=0.0035, respectively). These data suggest that Y-Box-binding protein-1 expression has clinicopathological significance with potential as a predictive marker of recurrence in nasopharyngeal cancer patients who undergo radiotherapy or chemoradiotherapy.