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Background: Over the last three years, the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a global impact. COVID-19 has led to diagnostic and treatment delays in head and neck squamous cell cancers (HNSCCs). Both cancer and COVID-19 trigger systemic inflammatory responses that can result in cytokine storms, creating a favorable tumor microenvironment that supports tumor growth. Various studies have shown a positive association between increasing neutrophil-to-lymphocyte ratio (NLR) and disease severity in COVID-19. Studies have also shown that high NLR is associated with poor survival outcomes in cancer patients. Our aim is to investigate whether an increased NLR is linked to rapid tumor progression in patients with HNSCC who have also been affected by infections like COVID-19 in the pre-operative period., Methods: This was a retrospective analysis of patients of HNSCC who were scheduled for surgery and had contracted COVID-19 in their pre-operative period between April 2021 and May 2021. The study analyzed pre- and post-COVID NLR in relation to disease progression in HNSCC. Statistical analysis was presented as an interquartile range and numbered with the percentage. Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, IBM Corp., Version 26.0, Armonk, NY) was utilized for the analysis., Results: We evaluated 200 operable cases of which 38/200 (20%) patients with HNSCC were COVID-19 positive. Out of those COVID-19-positive patients, 27/38 (71%) patients got operated. Around, 11/38 (28.9%) patients were inoperable. And, 14/27 (53.8%) operated patients also had a change in treatment plan. The mean duration from the joint clinic treatment plan to the date of surgery was 25.18 days. Patients who had contracted COVID-19 and had a change in their treatment plan due to disease progression exhibited mean NLR values of 3.84 (pre-COVID) and 11.11 (post-COVID), with respective medians of 3.04 and 10.50. These differences showed a statistically significant p-value of 0.000. In contrast, patients who had no change in treatment plan displayed mean NLR values of 4.51 (pre-COVID) and 9.70 (post-COVID), with respective medians of 3.47 and 3.42, resulting in with a non-significant p-value of 0.082., Conclusion: This is a one-of-its-kind study that has evaluated the role of elevated NLR in patients with a COVID-19 virus infection and its relationship with the clinical progression of the disease. The findings suggest that elevated NLR in patients with HNSCC, along with concurrent SARS-CoV2 infection, may contribute to accelerated disease progression with an increase in tumor burden and nodal metastasis., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethical Committee (MPMMCC) issued approval 2020/46. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sarkar et al.)