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Background: Overexpression of hypoxia-inducible factor-1α (HIF-1α) has been found to be significantly associated with the tumor invasion, lymph node metastasis, clinical stage, and prognosis of a variety of human cancers. Methods: This study examined the expression of HIF-1α in 57 specimens of oral squamous cell carcinoma (OSCC), 41 specimens of oral epithelial dysplasia (OED, 12 mild, 17 moderate, and 12 severe OED cases), and 14 specimens of normal oral mucosa (NOM) by immunohistochemistry. Results: We found that the mean nuclear HIF-1α labeling indices (LIs) increased significantly from NOM (9 ± 6%) through mild OED (25 ± 18%), moderate OED (41 ± 27%), and severe OED (42 ± 22%) to OSCC samples (55 ± 23%, P < 0.001). A significant correlation was found between the higher mean nuclear HIF-1α LI and OSCCs with larger tumor size ( P < 0.001), regional lymph node metastasis ( P < 0.001), or more advanced clinical stages ( P < 0.001). Only larger tumor size ( P = 0.002) and nuclear HIF-1α LI ≥ 60% ( P = 0.048) were identified as independent unfavorable prognosis factor by multivariate analyses with Cox regression model. Kaplan–Meier curve showed that OSCC patients with a nuclear HIF-1α LI ≥ 60% had a significantly poorer cumulative survival than those with a nuclear HIF-1α LI < 60% (log-rank test, P = 0.022). Conclusions: We conclude that the expression of HIF-1α is an early event in oral carcinogenesis. The nuclear HIF-1α LI in OSCC samples can predict the progression of OSCCs and the survival of OSCC patients. [ABSTRACT FROM AUTHOR]