Background: In patients with head and neck squamous cell carcinoma (HNSCC), curative-intent radiotherapy (RT) and chemoradiotherapy (CRT) are associated with substantial acute morbidity and 5-10% of patients die within 180 days of treatment initiation. Most of these early deaths occur without HNSCC recurrence or progression and may therefore be preventable to some extent. We developed a prediction tool to estimate the risk of non-HNSCC mortality occurring within the first 180 days following RT/ CRT initiation.Methods: Patients with HNSCC treated with RT/CRT, including postoperative RT/CRT, at Rigshospitalet or Herlev Hospitals between 2010-2017 were identified in the Danish Head and Neck Cancer Group (DAHANCA) database. Predictor variables included age, stage, performance status, tumor subsite including p16 status, comorbidity, postoperative status, smoking and pre-treatment albumin levels. The 180day non-HNSCC mortality risk was estimated by combining cause-specific Cox regression models.Results: We included 2209 patients. The 180-day non-HNSCC mortality rate was 4.4% and almost one third (31.6%) of non-HNSCC deaths were caused by pneumonia. After internal model validation, the area under the receiver operating curve was 0.74 (95% CI: 0.66-0.81) and calibration was good for risk predictions ranging from 0% to 20%.Conclusion: We developed a prediction tool to estimate the 180-day non-HNSCC mortality risk. This tool can be used to select high-risk patients for supportive interventions aiming to improve survival rates, and is available for interactive use at https://emriskpred.shinyapps.io/EMNED_App/. (c) 2022 The Authors. Published by Elsevier B.V. Radiotherapy and Oncology xxx (2022) xxx-xxx This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).