The critical molecular regulator of hypoxia is the hypoxia-inducible factor 1 alpha (HIF-1alpha). The prognostic impact of this regulator protein in oral squamous cell carcinomas (OSCC) has not been comprehensively investigated. The aim of this study was to analyze the expression of HIF-1alpha in 82 patients with OSCC and to correlate it with their disease-specific survival. Immunohistochemical staining for HIF-1alpha was performed on 82 OSCC specimens using a standard immunoperoxidase technique. The expression of HIF-1alpha was correlated with poor disease-specific survival for OSCC patients. Patients with negatively or weakly HIF-1alpha-expressing tumors had a survival rate of 80%, whereas the survival decreased to only 33.6% in case of moderate or strong expression. In multivariate Cox regression analysis, we found a 3.5-fold increased risk of tumor-related death when HIF-1alpha was strongly expressed (p=0.016) compared to negative or weak expression of HIF-1alpha. We suggest HIF-1alpha is an independent prognostic marker in OSCC. Immunohistochemical detection of HIF-1alpha appears to be useful in the diagnosis of OSCC and to provide prognostic information in addition to TNM stage and histological grade.