Blood-based protein biomarkers can be a useful tool as pre-treatment prognostic markers, as they can reflect both variations in the tumour microenvironment and the host immune response. We investigated the influence of a panel of plasma proteins for the development of any failure defined as recurrent disease in the T-, N-, or M-site in HNSCC. We used a multiplex bead-based approach to analyze 19 proteins in 86 HNSCC patients and 15 healthy controls. We evaluated the associations between the biomarkers, loco-regional failure, failure in the T-, N-, or M-site, overall survival (OS), p16 status, and hypoxia.