Inflammation and immune evasion are associated with carcinogenesis. Systemic Inflammation Response Index (SIRI) has been proposed as a pretreatment peripheral blood biomarker. The aim of this study is to analyze its prognostic capacity in head and neck squamous cell carcinomas (HNSCC). We performed a retrospective study in 824 patients with HNSCC. SIRI was calculated by neutrophils*monocytes/lymphocytes. Using a recursive-partitioning analysis considering disease-specific survival (DSS) as dependent variable, three categories were defined according to SIRI value. Males, patients with history of toxic consumption, oropharyngeal or hypopharyngeal tumors, and advanced tumors had a significantly higher SIRI value. As SIRI increased, a significant decrease in DSS was observed. In a multivariable analysis, SIRI was an independent predictor of DSS. Moreover, SIRI was a significant predictor of local, regional, and distant recurrence-free survival. SIRI has independent prognostic capacity in HNSCC. Patients with higher SIRI have a significant decrease in DSS. © 2019 Wiley Periodicals, Inc.