Head and neck squamous cell carcinoma (HNSCC), the sixth most common malignancy worldwide, is a disease with a profoundly high incidence of long-term morbidity as a result of current treatment protocols. Given the prevalence of this cancer type, reduction in debilitating treatment-related morbidities is of critical importance. HNSCC is comprised of two biologically distinct tumor types: Those caused by environmental factors such as smoking and alcohol consumption, and those caused by human papillomavirus (HPV). The purpose of this study was to conduct a comparison pathway enrichment analysis using the Gene Set Enrichment Analysis (GSEA) approach between three cancer cohorts: HPV-positive HNSCC, HPV-negative HNSCC, and HPV-positive cervical squamous cell carcinoma (CSCC).