Background and purpose: In head and neck squamous cell carcinoma (HNSCC) (chemo)radiotherapy is increasingly used to preserve organ functionality. The purpose of this study was to identify predictive pretreatment DWI- and 18F-FDG-PET/CT-parameters for treatment failure (TF), locoregional recurrence (LR) and death in HNSCC patients treated by (chemo)radiotherapy. Materials and methods: We retrospectively included 134 histologically proven HNSCC patients treated with (chemo)radiotherapy between 2012-2017. In 58 patients pre-treatment DWI and 18F-FDG-PET/CT were performed, in 31 patients DWI only and in 45 patients 18F-FDG-PET/CT only. Primary tumor (PT) and largest lymph node (LN) metastasis were quantitatively assessed for TF, LR and death. Multivariate analysis was performed for 18F-FDG-PET/CT and DWI separately and thereafter combined. In patients with both imaging modalities, positive and negative predictive value in TF and differences in LR and death, were assessed. Results: Mean follow-up was 25.6 months (interquartile-range; 14.0–37.1 months). Predictors of treatment failure, corrected for TNM-stage and HPV-status, were SUVmax-PT, ADCmax-PT, total lesion glycolysis (TLG-LN), ADCp20-LN (P = 0.049, P = 0.024, P = 0.031, P = 0.047, respectively). TLG-PT was predictive for LR (P = 0.003). Metabolic active tumor volume (MATV-PT) (P = 0.003), ADCGTV-PT (P < 0.001), ADCSD (P = 0.048) were significant predictors for death. In patients with both imaging modalities SUVmax-PT remained predictive for treatment failure (P = 0.049), TLG-LN for LR (P = 0.003) and ADCGTV-PT for death (P < 0.001). Higher predictive value for treatment failure was found for the combination of SUVmax-PT and ADCmax-PT, compared to either one separately. Conclusion: Both DWI- and 18F-FDG-PET/CT-parameters appear to have predictive value for treatment failure, locoregional recurrence and death. Combining SUVmax-PT and ADCmax-PT resulted in better prediction of treatment failure compared to single parameter assessment.