14-3-3σ an intracellular phosphoserine binding protein regulates different cellular signalling processes and is involved in cancer development. In this study, we examined the expression of 14-3-3σ and evaluated its clinical significance in OSCC.Tumour tissue from 95 OSCC patients was analysed for 14-3-3σ and p53 expression, respectively. The correlation of these proteins with survival and clinical parameters was assessed.14-3-3σ high expression was observed in 44.2% of OSCC patients. A significant role of 14-3-3σ expression on survival was shown by Kaplan–Meier analysis. Median survival time was 4.1years for patients with 14-3-3σ low tumours, compared with 1.36years for 14-3-3σ high tumours (P=.0021). Subset analysis in patients receiving adjuvant chemotherapy showed that the overall survival was significantly decreased in 14-3-3σ high tumours than in 14-3-3σ low tumours (P=.02). p53 expression was not significant in univariate analyses. In multivariate regression analysis, 14-3-3σ expression emerged as a significant independent parameter (P=.003).These results provide evidence that 14-3-3σ expression is involved in OSCC and, in contrast to p53 expression represents a new prognostic marker for OSCC and therapy response. Pending validation targeting 14-3-3σ might also be a new opportunity to improve therapy.