Objective: The aim of this study was to review the published literature and investigate whether sex determining region Y-box 2 (SOX2) is a prognostic factor in head and neck squamous cell carcinoma (HNSCC) by conduct a meta-analysis.Materials and Methods: Trials were identified from the major electronic databases (MEDLINE, EMBASE, and Cochrane Library) using the key words “HNSCC” and “SOX2.” The overall survival (OS), disease-specific survival (DPS), and disease-free survival (DFS) were the primary outcome measures.Results: We identified 371 articles, 9 articles 11 studies with a total number of 1334 cases were eligible for inclusion of this meta-analysis. The results showed that OS (DPS) in low-expression group was higher than that in high-expression group. However, the difference between the two groups was not significant (hazard ratio [HR] = 1.30, 95% confidence interval [95% CI] = [0.88, 1.91]; P = 0.18), and there was great statistical heterogeneity (I2 = 66%, P = 0.002). After subgroup analysis, the HR for OS of the patients with reduced expression of SOX2 was 1.34 (95% CI = [1.04, 1.74], P = 0.03), and the heterogeneity became acceptable (I2 = 32%, P = 0.16). The HR for DFS of the patients with reduced expression of SOX2 was 1.39 (95% CI = [1.00, 1.93]; P = 0.05).Conclusion: The findings of this meta-analysis are indicative of that high SOX2 expression is a negative prognostic factor of HNSCC and exhibit both worse OS and DFS. However, the small sample size available for this systematic review limited the power of this quantitative meta-analysis. It may therefore be too early to place complete confidence in these results.