Introduction: Systemic inflammation response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) have been proposed as peripheral blood biomarkers. We compared these blood biomarkers to identify the best predictor in patients with hypopharyngeal squamous cell carcinoma (HPSCC). Methods: We conducted a retrospective study on 304 patients with HPSCC. SIRI was divided into three groups using X-tile version 3.6.1. The optimal cut-off points for NLR, LMR, and PLR were selected through RStudio. We compared the prognostic capacity of SIRI with that of NLR, LMR, and PLR using receiver operating characteristic curves. Results: Smoking, cancer in the postcricoid region, lymph node metastasis (N+), extracapsular invasion, SIRI in the highest tertile (>2.80), and LMR in the lowest tertile (Conclusions: SIRI was a better predictor of OS than LMR, PLR, and NLR in HPSCC patients. SIRI in the highest tertile (>2.80) and LMR in the lowest tertile (