Head and neck squamous cell carcinomas are heterogeneous neoplasms that show clinical and biological differences in association with the human papillomavirus (HPV). To provide adequate therapeutic strategies, biological and clinical characterization is essential to stratify patients based on prognostic and predictive factors. Reports on HNSCC are scarce in Mexico, thus in the present study, we analyze 414 cases of HNSCC, including those of the oropharynx (OPSCC), larynx (LASCC), and oral cavity (OCSCC). We determined the presence of HPV and p16 expression. Global expression profiles were analyzed with Affymetrix HTA 2.0 microarray in 25 selected cases HPV+/p16+ versus HPV-/p16-. In our study we analyze 25 samples derived from HNSCC patients. 18 samples were HPV-/p16- and 7 HPV+/p16+. We compared the HPV-/p16- versus the HPV+/p16+ and identified differentially expressed RNAs with a fold change greater than 1.5 or less than -1.5. These data were used to obtain 98 genes that are differentially expressed in absence of HPV. The present study offers information regarding clinical and molecular characteristics of HNSCC, both associated and unassociated with HPV, in Mexican patients. Overall design: 25 total samples were analyzed. The samples were collected from Unidad Médica de Alta Especialidad de Oncología del Centro Médico Nacional Siglo XXI, of the Instituto Mexicano del Seguro Social (Mexican Social Security Institute). We compared HPV+/p16+ and HPV-/p16- of patients with HNSCC . A fold change greater than 1.5 or less than -1.5 and a p-value ≤ 0.05 were used to compare gene expression.