We previously demonstrated that 15-LOX-2 is significantly reduced in head and neck carcinoma and restoration of 15-LOX-2 expression results in tumor inhibition in HNC. The aim of this study is to evaluate 15-LOX-2 as a candidate for targeted radiotherapy. Molecular subcloning was performed to create a radiation-inducible 15-LOX-2 expression vector in which the full-length 15-LOX-2 cDNA was inserted downstream the recombinant Egr-1 promoter. The radiation-induced downregulations of 15-LOX-2 protein (twofold up) and its main metabolite 15S-HETE (threefold up) were observed in HNC cells transfected with the 15-LOX-2 expression vector after 4 Gy of radiation. Radiation-induced upregulation of 15-LOX-2 resulted in significant induction of apoptosis in HNC cells. Furthermore, survival colony formation was significantly reduced by 4 Gy in the HNC cells containing the 15-LOX-2 expression vector compared with the controls. Radiation-induced upregulation of 15-LOX-2 results in significant induction of apoptosis and enhances killing effect of radiotherapy in HNC. In addition, exogenous addition of 15S-HETE at high concentrations (>/=10 muM) but not at low concentrations induced upregulation of its endogenous ligand PPARgamma. In conclusion, synergistic effect between radiation and 15-LOX-2 was observed in killing HNC. 15-LOX-2 may be a potential target in radiation-targeted therapy of HNC. The 15-LOX-2 inhibition may not be PPARgamma dependent.