Oral squamous cell carcinoma (SCC) can be vascularized through a process called "tumor cell-lined vessels". Currently, the tumor microenvironment, which is recognized as hypoxic and orchestrated largely by inflammatory cells and defective blood vessels, is considered an important participant in the neoplastic process. We sought to determine their clinicopathologic significance and prognostic implication in oral SCC. Vascular structure was investigated by multistaining with pan-cytokeratin, CD34, and alpha-smooth actin/type IV collagen. Immunohistochemical staining of the hypoxia inducible factor-1 alpha (HIF-1 alpha) and CD68 was used to reflect hypoxia and tumor-associated macrophages (TAM). Our results showed that in a high percentage of vessels in cancer tissue. There is absence of pericyte coverage and loss of basement membrane lining. Significant association between the integrity of vascular structure and lymph node involvement and presence of tumor cell-lined vessel was found. HIF-1 alpha overexpression was frequently observed in cancer cells (78/112) and correlated with tumor progress index. In cancer tissues, the TAM ranged from 28 to 296 cells/mm2 with a mean of 144.6+/-64.3 cells/mm2. There was a significant correlation between TAM and lymph node involvement (P=0.004) and tumor size (P=0.004). Also, a close association was found between TAM count and integrity of vascular structure. In addition, survival analysis revealed that tumor cell-lined vessels (P=0.001), HIF-1 alpha expression (P=0.004), and TAM (P=0.001) correlated significantly with poor survival. We conclude that in the cancer microenvironment, HIF-1 alpha expression and the TAM are induced and contributed to malignant behavior of tumor cells. Furthermore, the presence of tumor cell-lined vessel, HIF-1 alpha overexpression, and high TAM could be the potential markers of prognosis for patients with oral SCC.