Background. Tumour hypoxia and a high tumour metabolism increase radioresistance in patients with head and neck squamous cell carcinoma (HNSCC). The aim of this study was to evaluate the correlation between hypoxia ([F-18]HX4 PET) and glucose metabolism ([F-18]FDG PET) molecular imaging.Material and methods. [F-18]HX4 and [F-18]FDG PET/CT images of 20 HNSCC patients were acquired prior to (chemo)radiotherapy, in an immobilisation mask, with a median time interval of seven days (NCT01347281). Gross tumour volumes of the primary lesions (GTV(prim)) and pathological lymph nodes (GTV(ln)) were included in the analysis. [F-18]FDG PET/CT images were rigidly registered to the [F-18]HX4 PET/CT images. The maximum and mean standardised uptake values (SUVmax, SUVmean) within both GTVs were determined. In addition, the overlap was compared between the [F-18]HX4 high volume ([F-18]HX4 HV) with a tumour-to-muscle ratio > 1.4 and the [F-18]FDG high volume ([F-18]FDG HV) with an SUV > 50% of the SUVmax. We report the mean standard deviation.Results. PET/CT scans including 20 GTV(prim) and 12 GTV(ln)were analysed. There was a significant correlation between several [F-18]FDG and [F-18]HX4 parameters, the most pronounced being the correlation between [F-18]FDG HV and [F-18]HX4 HV (R = 0.93, p <0.001). The fraction of the GTV(prim) with a high HX4 uptake (9 +/- 10%) was on average smaller than the FDG high fraction (51 +/- 26%; p <0.001). In 65% (13/20) of the patients, the GTV(prim) was hypoxic. In four of these patients the [F-18]HX4 HV was located within the [F-18]FDG HV, whereas for the remaining nine GTV(prim) a partial mismatch was observed. In these nine tumours 25 +/- 21% (range 5-64%) of the HX4 HV was located outside the FDG HV.Conclusions. There is a correlation between [F-18]HX4 and [F-18]FDG uptake parameters on a global tumour level. In the majority of lesions a partial mismatch between the [F-18]HX4 and [F-18]FDG high uptake volumes was observed, therefore [F-18]FDG PET imaging cannot be used as a surrogate for hypoxia. [F-18]HX4 PET provides complementary information to [F-18]FDG PET imaging.