Background: Neutrophil-to-lymphocyte ratio (NLR) is an easily attainable biomarker that is correlated with systemic inflammation and identifies increased risk of treatment complications and decreased survival in patients with cancer. Our objective was to investigate the use of NLR as an independent prognostic predictor of survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with cisplatin chemotherapy. Methods: We conducted a retrospective study of 2,084 patients in the Veterans Health Affairs system with stages III–IVB head and neck squamous cell carcinoma diagnosed between 2000–2014 and treated with cisplatin-based chemoradiotherapy for curative intent. We calculated NLR values from laboratory values collected in the 30 days prior to initiation of chemoradiotherapy and dichotomized NLR using the Youden J-statistic (NLR = 3.64). We then compared outcomes using Cox proportional hazards methods, adjusting for sociodemographic characteristics (age, race, and sex), date of cancer diagnosis, smoking status, alcohol use, primary site of tumor, tumor characteristics (overall stage, T stage, and N stage), comorbidity score, eGFR, baseline neuropathy and hearing loss, BMI, and oncologic surgical procedures. Results: The cohort had a median age of 61. 99% of cases were male, 82% were white, 13% were black, and 4% were Hispanic. 36% of cases had an NLR > 3.64 prior to treatment initiation. Median overall survival was 32.6 months for the low-NLR group and 24.9 months for the high-NLR group. In unadjusted analyses, a high NLR was associated with an increased risk of all-cause death (hazard ratio [HR]: 1.21; 95% CI 1.08–1.34). In adjusted analyses, high NLR retained significance and predicted overall survival (HR: 1.15; 95% CI 1.02–1.30). We also performed a secondary analysis for death within six months of cancer diagnosis; high NLR was associated with > 50% increased risk of death after adjustment (HR: 1.56; 95% CI 1.04–2.33). Conclusions: In this large cohort of Veterans with advanced HNSCC undergoing chemoradiotherapy, NLR was an independent prognostic predictor of survival. NLR may be a useful clinical risk stratification tool prior to chemoradiotherapy initiation.