Background and purpose: Hypoxia Positron-Emission-Tomography (PET) as well as Computed Tomography (CT) radiomics have been shown to be prognostic for radiotherapy outcome. Here, we investigate the stratification potential of CT-radiomics in head and neck cancer (HNC) patients and test if CT-radiomics is a surrogate predictor for hypoxia as identified by PET. Materials and methods: Two independent cohorts of HNC patients were used for model development and validation, HN1 (n = 149) and HN2 (n = 47). The training set HN1 consisted of native planning CT data whereas for the validation cohort HN2 also hypoxia PET/CT data was acquired using [ 18 F]-Fluoromisonidazole (FMISO). Machine learning algorithms including feature engineering and classifier selection were trained for two-year loco-regional control (LRC) to create optimal CT-radiomics signatures. Secondly, a pre-defined [ 18 F]FMISO-PET tumour-to-muscle-ratio (TMR peak ≥ 1.6) was used for LRC prediction. Comparison between risk groups identified by CT-radiomics or [ 18 F]FMISO-PET was performed using area-under-the-curve (AUC) and Kaplan-Meier analysis including log-rank test. Results: The best performing CT-radiomics signature included two features with nearest-neighbour classification (AUC = 0.76 ± 0.09), whereas AUC was 0.59 for external validation. In contrast, [ 18 F]FMISO TMR peak reached an AUC of 0.66 in HN2. Kaplan-Meier analysis of the independent validation cohort HN2 did not confirm the prognostic value of CT-radiomics (p = 0.18), whereas for [ 18 F]FMISO-PET significant differences were observed (p = 0.02). Conclusions: No direct correlation of patient stratification using [ 18 F]FMISO-PET or CT-radiomics was found in this study. Risk groups identified by CT-radiomics or hypoxia PET showed only poor overlap. Direct assessment of tumour hypoxia using PET seems to be more powerful to stratify HNC patients.