To develop and validate a radiogenomics model integrating clinical data, radiomics-based machine learning (RBML) classifiers, and transcriptomics data for predicting the response to induction chemotherapy (IC) in patients with head and neck squamous cell carcinoma (HNSCC).Radiomics features derived from T2-weighted, pre- and post-contrast-enhanced T1-weighted MRI sequences, clinical data, and RNA sequencing data of 150 patients with HNSCC were included in the study. Analysis of variance or recursive feature elimination was used to reduce radiomics features. Three RBML classifiers were developed to distinguish non-responders from responders. Weighted correlation network analysis (WGCNA) was performed to identify the correlation between clinical data or radiomics features and molecular features; subsequently, protein interaction and functional enrichment analyses were performed. The predictive performance of the radiogenomics model integrating significant clinical variables, RBML classifiers, and molecular features was evaluated using receiver operating characteristic curve analysis.Five radiomics features and two conventional MRI findings significantly stratified HNSCC patients into responders and non-responders. On WGCNA analysis, 809 genes showed a significant correlation with two radiomics features. Functional enrichment analysis suggested that our proposed radiomics features could reflect the T cell-mediated immune response and immune infiltration of HNSCC. The radiogenomics model showed the highest area under the curve (0.88[95%CI 0.75-0.96]) for predicting IC response, which was better than MRI findings(p = 0.0407) or molecular features(p = 0.004) alone, but showed no significant difference with that of RBML model (p = 0.2254) in test cohort.Merging imaging phenotypes with transcriptomic data improved the prediction of IC response in HNSCC.Copyright © 2023 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.