Increasing evidence has demonstrated that glucose-6-phosphate dehydrogenase (G6PD), a key metabolic enzyme, participating in pentose phosphate pathway (PPP), is tightly associated with development and progression of a variety of tumors. Here, we reported expression of G6PD and its association with the prognosis of the patients with esophageal squamous cell carcinoma (ESCC). The results revealed significantly elevated G6PD mRNA and protein expressions in ESCC tissues compared with normal tissues (P < 0.05). Furthermore, high G6PD expression was tightly associated with histological grade, TNM staging and lymph node metastasis (P < 0.05), but not related to the patients' age and gender (P > 0.05). Importantly, the survival time of G6PD-positive patients was markedly lower than that of G6PD-negative patients (P < 0.05). Most notably, Cox multivariate assay demonstrated that G6PD was an independent prognostic factor for the patients with ESCC. In conclusion, G6PD may be a novel predictor for the prognosis of the patients with ESCC.