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Radiotherapy is the principal modality used to treat early stage laryngeal cancer. Unfortunately treatment failures occur in 10–25% of patients. Subsequent salvage surgery is technically more difficult, with increased complication and failure rates. The ability to predict or prevent radioresistance would improve the poor survival associated with this disease. Cox-2 is an inducible enzyme involved with prostaglandin synthesis. We investigated a potential role for Cox-2 in predicting radioresistance in laryngeal cancer.Using immunohistochemical techniques we examined the expression of Cox-2 protein in 122 pre-treatment laryngeal biopsies. All tumours were treated with single modality radiotherapy (curative intent). The group comprised of 61 radioresistant and 61 radiosensitive tumours matched for T stage, laryngeal subsite, gender and smoking history.Cox-2 expression was detected in 41 of 61 (67%) biopsy samples from patients with radioresistant tumours and 25 of 61 (41%) radiosensitive tumours. Overexpression was significantly associated with radioresistant tumours (P=0.004). Cox-2 has a 67% accuracy in predicting radiotherapy failure.Cox-2 may have prognostic value in predicting response to radiotherapy. Cox-2 inhibitors such as NS-398 have been shown to enhance the effects of radiotherapy. We suggest that their use may be beneficial in patients who are destined to fail radiotherapy.