High CD40LG expression was linked to higher RS values, while HNSCC patients with lower RS values fared poorly.<h4>Conclusions</h4>The study concludes that a contrast-enhanced CT-based radiomics model can accurately predict CD40LG expression and prognosis in HNSCC patients, aiding in clinical decision-making.<h4>Level of evidence</h4>Level 4. This evidence concerns the gene CD40LG and head and neck squamous cell carcinoma.