ABSTRACT JOURNAL/crsat/04.03/02201859-202306020-00007/figure1/v/2023-08-03T140821Z/r/image-tiff JOURNAL/crsat/04.03/02201859-202306020-00007/figure2/v/2023-08-03T140821Z/r/image-tiff Background: Head-and-neck squamous cell carcinomas (HNSCC) comprise 30% of all cancer cases in India. The risk factors for HNSCC include tobacco and alcohol consumption. Objectives: Our primary objective was to evaluate the epidemiological profile of patients with HNSCC in the western Tamil Nadu population. Our secondary objective was to assess the association of the epidemiological profile with different anatomical sites and risk factors. Materials and Methods: This was a cross-sectional study of data compiled from the clinical records of Sri Ramakrishna Institute of Oncology and Research Department, Sri Ramakrishna Hospital, Coimbatore (Tamil Nadu, India) from January 2018 to December 2021. Clinicodemographic data like age, sex, primary tumor site, clinical staging, family history, and exposure to risk factors (smoking, tobacco chewing, alcohol) were collected from patients with histologically confirmed HNSCC using a specially designed questionnaire. Human papillomavirus (HPV) status was determined by p16 immunohistochemistry and validated using polymerase chain reaction (PCR) by employing consensus primers for HPV deoxyribonucleic acid (DNA). Results: We enrolled 150 patients. The male-to-female ratio was 3:1. The mean age was 54.4 ± 10.2 years; majority of patients (59 [39.3%]) were aged between 51 and 60 years. The most frequently affected site was the oral cavity (58 [38.7%]). Tobacco chewing was the most common and the only risk factor observed among female patients (23 [62.2%]), while smoking along with alcohol consumption was commonly observed among male patients (24 [21.2%]). Smoking in combination with other risk factors (44 [29.3%]) was more common than smoking alone (9 [8%]). Tobacco chewing was a predominant risk factor for nasopharyngeal (4 [63.6%]) and oral cavity cancer (19 [32.8%]), while smoking was a predominant risk factor for laryngeal cancer (3 [30%]). Smoking with alcohol consumption was largely seen in oropharyngeal cancer (5 [33.3%]), while all three risk factors were observed in hypopharyngeal cancer (4 [14.3%]). Out of 38 samples tested, only four were positive for HPV (10.5%). Conclusions: The most affected demographic group with regard to HNSCC is middle-aged men (51–60 years), and the oral cavity is the most commonly affected site. Tobacco chewing is the most prevalent risk factor among women while smoking and alcohol consumption are the most common risk factors among men. Spreading awareness about the risk factors of HNSCC and their prevention is crucial to optimizing disease control.