Hypoxia has long been recognized as detrimental to the successful treatment of malignant tumors with ionizing radiation. Because hypoxia-inducible factor (HIF)-1α plays an essential role in oxygen homeostasis in vitro, we explored the predictive potential of this factor in a cohort of 98 patients with squamous cell cancer of the oropharynx, who were treated by curative radiation therapy. Ninety-four % of the primary tumors showed overexpression of HIF-1α, relative to the surrounding tissue, as determined by immunohistochemistry. The degree of HIF-1α immunoreactivity correlated inversely with both the rate of complete remission of the primary tumor (odds ratio, 0.33; P = 0.03) and lymph node metastases (odds ratio, 0.34; P = 0.02) as well as with local failure-free survival (risk ratio, 2.15; P = 0.006), disease-free survival (risk ratio, 2.01; P = 0.008), and overall survival (risk ratio, 2.17; P = 0.002). The multivariate analysis revealed the predictive power of HIF-1α to be independent of other covariables. We conclude that HIF-1α is overexpressed in the vast majority of patients with squamous cell cancer of the oropharynx and that the degree of expression has predictive and prognostic significance in individuals undergoing curative radiation therapy.