Head and neck squamous cell carcinoma (HNSCC) is a cancer with well-defined tumor causes such as HPV infection, smoking and drinking. Using The Cancer Genome Atlas (TCGA) HNSCC cohort we systematically studied the mutational load as well as patterns related to patient age in HNSCC. To obtain a homogenous set we excluded all patients with HPV infection as well as wild type TP53. We found that the overall mutational load is higher in patients of old age. Through unsupervised hierarchical clustering, we detected distinct mutational clusters in very young as well as very old patients. In the group of old patients, we identified four enriched pathways ("Axon Guidance", "ECM-Receptor Interaction", "Focal Adhesion" and "Notch Signaling") that are only sporadically mutated in the other age groups. Our findings indicate that the four pathways regulate cell motility, tumor invasion and angiogenesis supposedly leading to less aggressive tumors in older age patients. Importantly, we did not see a strict pattern of genes always mutated in older age but rather an accumulation of mutations in the same pathways. Our study provides indications of age-dependent differences in mutational backgrounds of tumors that might be relevant for treatment approaches of HNSCCs patients.