Background: Lymphocyte-monocyte ratio (LMR) from peripheral blood has been suggested as a biomarker to assess the extent of inflammation in several solid malignancies. However, the role of LMR as a prognostic factor in head and neck cancer (HNC) was unclear in several meta-analyses, and there is a paucity of literature including patients in North America. We performed an observational cohort study to evaluate the association of pre-radiation LMR with survival outcomes in North American patients with HNC. Methods: A single-institution database was queried for patients with non-metastatic HNC who underwent curative-intent definitive chemoradiation from 6/2007 to 4/2021 at the Roswell Park Comprehensive Cancer Center. Patients were excluded if they underwent induction chemotherapy or postoperative radiation. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). The association of LMR with OS and CSS was examined using nonlinear Cox proportional hazard model using restricted cubic splines (RCS), Cox multivariable analysis (MVA), and Kaplan-Meier method. LMR was stratified into high and low based on its median. Logistic MVA was performed to identify variables associated with low LMR. Propensity scored matching was used to reduce selection bias. Subgroup analyses were performed among those with available human papillomavirus (HPV) status. Results: A total of 476 patients (391 male [82.1%], median [interquartile range] age, 61 [55-67] years) met our criteria. Median follow up was 45.3 months (interquartile range 22.8-74.0). The nonlinear Cox regression model using RCS showed that low LMR was associated with worse OS and CSS in a continuous fashion without plateau and crossed the hazard ratio of 1 at LMR 3.4 for both OS and CSS. On Cox MVA, higher LMR as a continuous variable was associated with improved OS (adjusted hazard ratio [aHR] 0.90, 95% confidence interval [CI] 0.82-1.00, p = 0.04) and CSS (aHR 0.81, 95% CI 0.70-0.94, p = 0.005). The median value of LMR was 3.8. On logistic MVA, patients with other racial background (adjusted odds ratio [aOR] 0.85, 95% CI 0.74-0.97, p = 0.02) and positive HPV status (aOR 0.82, 95% CI 0.72-0.94, p = 0.005) were less likely to have low LMR. Higher T staging was associated with low LMR (aOR 1.15, 95% CI 1.04-1.27, p = 0.005). A total of 186 pairs were matched with well balanced baseline characteristics. LMR lower than 3.8 remained associated with worse OS (HR 1.60, 95% CI 1.13-2.28, p = 0.009) and CSS (HR 1.69, 95% CI 1.07-2.67, p = 0.03). In the subgroup of 319 patients (67.0%) with available HPV data, LMR status was not associated with both OS and CSS regardless of HPV status. Conclusions: Low LMR was associated with worse OS and CSS. Low LMR was also associated with higher T staging, negative HPV status, and White race. Further studies are warranted to evaluate the role of such prognostic marker to tailor interventions.