Analysis of the tumor microenvironment has been proposed as a strategy for the treatment and prognosis of different neoplastic processes. A grading system based on the tumor-stroma ratio (TSR), which evaluates the proportion of stroma in relation to neoplastic parenchyma at the invasion front, has shown a strong prognostic value in different neoplastic processes. The aim of the present systematic review was to understand the role of the TSR in head and neck squamous cell carcinoma (HNSCC), evaluating its correlation with clinical and prognostic parameters. An electronic search was performed in PubMed/Medline, Web of Science, Science Direct, Scopus, Embase, and the Cochrane Collaboration Library. Publications assessing the relationship between TSR and prognosis in cases of HNSCC were eligible. The quality of the studies was assessed independently by four evaluators using the Newcastle-Ottawa scale. After application of the previously es+lished inclusion/exclusion criteria, nine articles were included in the qualitative synthesis. With regards to quality on the Newcastle-Ottawa scale, an overall value of 4.55 was obtained. This systematic review demonstrated a strong association between TSR and prognosis in esophageal and oral squamous cell carcinomas. Histopathological analysis of the TSR can optimize the analysis of the prognosis of cases diagnosed with HNSSC. In addition, the TSR is a reliable and simple parameter that can be evaluated in hematoxylin/eosin-stained slides during routine laboratory examinations, showing high inter- and intraobserver agreement.