Patients with (previous) head and neck cancer (HNC) are at high risk for developing second squamous cell cancer of the oesophagus. The role of cyclooxygenase-2 (COX-2) in oesophageal squamous carcinogenesis has not yet been investigated in this high-risk group. Therefore, this study examined COX-2 mRNA and protein expression in oesophageal biopsies and resected tissues of 44 HNC patients. The evaluation covered 55 oesophageal tissue samples (18 invasive oesophageal squamous cell cancers, four high-and eight low-grade dysplasias, 25 normal squamous epithelia) from the 44 patients. mRNA levels of COX-2 were measured by real-time PCR using a LightCycler. COX-2 protein expression was studied immunohistochemically and graded by a staining score. COX-2 mRNA was detected in all samples, and its levels correlated positively with the immunohistochemical staining score (Po0.05). COX-2 expression was upregulated during oesophageal squamous carcinogenesis in HNC patients, that is COX-2 expression increased significantly from normal oesophageal squamous epithelium to low-and high-grade dysplasia and finally to invasive squamous cell cancer (Po0.001). Our findings suggest that COX-2 upregulation contributes to oesophageal squamous carcinogenesis in HNC patients. Prospective studies are needed to evaluate the chemopreventive potential of COX-2 inhibitors in this high-risk group.