This study sought to determine the expression of angiopoietin-2 (Ang-2) and vascular endothelial cell growth factor (VEGF) in oral squamous cell carcinoma (OSCC) and assess their correlations with tumor progression, angiogenesis, vessel maturation, and clinical survival. Tumor tissue from 102 OSCC patients, adjacent noncancerous oral tissue from 79 OSCC patients, and normal oral mucosa from 35 control patients were examined for Ang-2 and VEGF expression using conventional immunohistochemistry. Microvessel density (MVD) and vessel maturation index (VMI) were assessed by double-label immunohistochemistry staining using anti-CD34 and anti-alpha-smooth muscle actin, respectively. Although the proportion of OSCC samples positive for Ang-2 or VEGF expression was significantly higher than that observed in the adjacent noncancerous tissue and normal oral mucosa (P < 0.001), neither Ang-2 nor VEGF expression was associated with the clinicopathological parameters analyzed in OSCC patients. However, MVD and VMI were significantly associated with the expression of Ang-2 (P = 0.001 and P = 0.014, respectively); VEGF expression was associated MVD (P = 0.004). The MVD of OSCC tissues expressing both Ang-2 and VEGF was significantly higher than observed in the double-negative samples (P < 0.05). Multivariate regression and Kaplan-Meier analyses revealed that Ang-2 was negatively associated with the overall survival of OSCC patients. Expression of Ang-2 was associated with angiogenesis and vessel maturation in OSCC. Further studies will evaluate the prognostic value of determining Ang-2 expression in OSCC.