The purpose of the study was to evaluate [(18)F]fluoromisonidazole (FMISO) PET in advanced head and neck cancer during hypoxia-targeting therapy.Fifteen of 16 patients in a phase I trial of chemoradiation plus tirapazamine (specific cytotoxin for hypoxic cells) in advanced (T3/4 and/or N2/3) head and neck cancer underwent serial [(18)F]fluorodeoxyglucose (FDG) and FMISO PET. We have previously reported excellent early clinical outcome of these patients and now review FMISO PET results in the context of longer follow-up of this patient cohort.Based on blinded qualitative scoring by two readers, FMISO PET was positive in 13/15 patients at baseline: 12/15 of primary sites and 8/13 neck nodes were scored as positive. All sites of corresponding FDG and FMISO abnormality at baseline showed marked qualitative reduction of uptake within 4 weeks of commencing therapy, consistent with effective hypoxia-targeted therapy. With a median follow-up of 6.9 years, there have been only four locoregional failures, while three other patients have died of metachronous lung cancer. The 5-year overall survival was 50% (95% CI 27-73%), the 5-year failure-free survival was 44% (95% CI 22-68%) and the 5-year freedom from locoregional failure was 68% (95% CI 38-88%).The high prevalence of hypoxia demonstrated on FMISO PET imaging is consistent with the advanced disease stage of these patients and would be expected to predict an adverse prognosis. Evidence of the early resolution of FMISO abnormality during treatment, associated with excellent locoregional control in this patient cohort, supports further investigation of hypoxia-targeting agents in advanced head and neck cancer.