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Background: Definitive chemoradiation is the primary treatment for locally advanced head and neck carcinoma (LAHNSCC). Optimising outcome predictions requires validated biomarkers, since TNM8 and HPV could have limitations. Radiomics may enhance risk stratification., Methods: This single-centre observational study collected clinical data and baseline CT scans from 171 LAHNSCC patients treated with chemoradiation. The dataset was divided into training (80%) and test (20%) sets, with a 5-fold cross-validation on the training set. Researchers extracted 108 radiomics features from each primary tumour and applied survival analysis and classification models to predict progression-free survival (PFS) and 5-year progression, respectively. Performance was evaluated using inverse probability of censoring weights and c-index for the PFS model and AUC, sensitivity, specificity, and accuracy for the 5-year progression model. Feature importance was measured by the SHapley Additive exPlanations (SHAP) method and patient stratification was assessed through Kaplan-Meier curves., Results: The final dataset included 171 LAHNSCC patients, with 53% experiencing disease progression at 5 years. The random survival forest model best predicted PFS, with an AUC of 0.64 and CI of 0.66 on the test set, highlighting 4 radiomics features and TNM8 as significant contributors. It successfully stratified patients into low and high-risk groups (log-rank p < 0.005). The extreme gradient boosting model most effectively predicted a 5-year progression, incorporating 12 radiomics features and four clinical variables, achieving an AUC of 0.74, sensitivity of 0.53, specificity of 0.81, and accuracy of 0.66 on the test set., Conclusion: The combined clinical-radiomics model improved the standard TNM8 and clinical variables in predicting 5-year progression though further validation is necessary., Key Points: Question There is an unmet need for non-invasive biomarkers to guide treatment in locally advanced head and neck cancer. Findings Clinical data (TNM8 staging, primary tumour site, age, and smoking) plus radiomics improved 5-year progression prediction compared with the clinical comprehensive model or TNM staging alone. Clinical relevance SHAP simplifies complex machine learning radiomics models for clinicians by using easy-to-understand graphical representations, promoting explainability., Competing Interests: Compliance with ethical standards. Guarantor: The scientific guarantor of this publication is Professor Andrés Cervantes. INCLIVA Biomedical Research Institute. Conflict of interest: Anna Nogué, Ana Jiménez-Pastor, Fuensanta Bellvís, Almudena Fuster-Matanzo, and Ángel Alberich-Bayarri declare relationships (full or part-time employment) with the following companies: QUIBIM SL. All other authors have declared no relationships with any companies, whose products or services may be related to the subject matter of the article. Statistics and biometry: One of the authors (Ana Jiménez-Pastor) has significant statistical expertise. Informed consent: Written informed consent was obtained from all patients in this study. Ethical approval: IRB approval was obtained (Ethics Committée of Clinical Research of the University Clinical Hospital of Valencia). Methodology: Prospective and retrospective Observational and prognostic study Performed at one institution, (© 2024. The Author(s).)