OBJECTIVE: Neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) are inflammatory markers easily obtained from a routine complete blood count, and their preoperative values have recently been correlated with oncological outcomes in patients with HPV-negative head and neck squamous cell carcinoma (HNSCC). The aim of this study is to evaluate the prognostic value of NLR and LMR before and after treatment in patients with HPV-negative HNSCC undergoing up-front surgical treatment. METHODS: This multicentric retrospective study was performed on a consecutive cohort of patients treated by upfront surgery for HPV-negative HNSCC between April 2004 and June 2018. Only patients whose pre- and postoperative NLR and LMR were available were included. Their association with local, regional and distant failure, progression-free survival (PFS) and overall survival (OS) was calculated. RESULTS: A total of 493 patients (mean age 68 years) were enrolled. The mean follow-up time was 54 months. Pre-surgical NLR ≥ 3.76 was associated with a high risk of regional failure (HR = 2.21, 95% CI: 1.08-5.55), disease progression (HR = 1.55, 95% CI: 1.07-2.25) and death (HR = 1.40, 95% CI: 0.94-2.10). A post-surgical LMR <
2.92 had a significant impact on disease progression (HR = 1.92, 95% CI: 1.13-3.28) and OS (HR = 2.98, 95% CI: 1.53-5.81). Patients with stable NLR ≥ 3.76 in the pre- and postoperative period had worse OS and PFS. CONCLUSIONS: Our results support that pre- and postoperative NLR and LMR can be useful in identifying patients at risk of local, regional, or distant recurrence who may require closer follow-up or more aggressive treatment.