Sox2 is a marker of embryonic stem cell pluripotency and plays an important role in tumor progression. However, Sox2 expression in oral tongue squamous cell carcinoma (OTSCC) and its correlation with patients' prognosis have not been investigated so far. In this study, we detected the expression of Sox2 in 82 patients with histologically node-negative (pN0) OTSCC by immunohistochemistry, and evaluated its correlation with clinicopatologic factors and disease prognosis. Sox2 positive expression was detected in 62.2% patients and showed a significant association with large tumor size. Survival analysis showed that patients with Sox2 positive expression had significantly poorer overall, cancer-specific and disease-free survivals than those with Sox2 negative expression at 5years after operation (P=0.004, 0.004 and 0.001, respectively). Multivariate analysis demonstrated that Sox2 positive expression was an independent prognosticator of unfavorable overall, cancer-specific and disease-free survivals (P=0.032, 0.035 and 0.011, respectively). According to our results, Sox2 positive expression was frequent in pN0 OTSCC and involved in tumor progression. The measurement of Sox2 expression may be helpful in predicting relapse and prognosis of patients with pN0 OTSCC.