Background: Since 2004, the use of the monoclonal antibody cetuximab has been preferred over platinum-based therapy for patients with advanced Head and neck squamous cell carcinoma (HNSCC). However, the response rate to the treatment is only around 20%. Currently, no biomarkers have been identified to differentiate potential responders from non-responders to cetuximab therapy.Methods: We evaluated the predictive and prognostic properties of AurkA polymorphism and HPV infection in HNSCC patients treated with cetuximab. Clinical data of 434 patients was collected and tissue was analyzed for AurkA polymorphism using PCR. Immunohistochemistry was used to stain for various markers and their expression levels were scored. Cell culture experiments were performed to complement clinical findings.Results: We demonstrated in vivo as well as in vitro that both AurkA polymorphism and HPV status have predictive and prognostic value. Conclusions: AurkA polymorphism and HPV status could be beneficial for response prediction and therapy optimization for HNSCC patients.