The aim of this study was to investigate the effects of combining antiangiogenic treatment, epidermal growth factor receptor (EGFR) targeting and irradiation (RT). We evaluated AZD2171, a highly potent, orally active, vascular endothelial growth factor (VEGF) signalling inhibitor, gefitinib, an EGFR tyrosine kinase inhibitor and RT. The antitumour efficacy of these treatments, administered alone and in combination for 2 weeks, was assessed in a VEGF-secreting human head and neck tumour cell line, CAL33 that highly expresses EGFR, established as xenografts (250 mm(3)) in nude mice. The median time to reach a tumour volume of 1000 mm(3) was significantly increased for AZD2171 or gefitinib alone compared with the control. Greater inhibition of tumour growth was seen with the combination of AZD2171+gefitinib compared with either drug alone, and the triple combination compared with either AZD2171+gefitinib or RT alone. The intensity of endothelial cell staining was slightly reduced by each agent given alone, and markedly diminished by the double or triple combination. The triple combination almost completely abolished cell proliferation. The marked RT-induced enhancement in the DNA-repair enzyme ERCC1 expression was totally abolished by the triple combination. This observation could help to explain the supra-additive antitumour effect produced by this combination and could provide a basis for future innovative clinical trials.