Background: Head and Neck Squamous Cell Carcinomas (HNSCC) is the sixth most common cancer globally. In India, on an average 25-30% of all cancer cases affect the head and neck. The etiological factors associated with HNSCC are tobacco, alcohol and environmental carcinogens. However there are few cases, where there are no obvious risk factors involved. In western counties, there are many reports of human papilloma virus (HPV) association with HNSCC. Hence, we conducted a study to determine the role of HPV infection and risk factors among patients with HNSCC. Materials and Methods: A prospective, cross-sectional study was conducted in a tertiary referral centre from January 2014 to March 2016. 88 patients were enrolled in the study. Socio- demographic, behavioural data, site and subsite involvement, histopathology, staging and treatment were documented. Polymerase chain reaction (PCR) was performed to detect the presence of HPV DNA using consensus primers MY 09/11 and GP5+/GP6+ and further the samples were subjected to PCR for detecting HPV type 16 and 18. Results: The study included 88 participants with HNSCC. 57 had oral and oropharyngeal squamous cell carcinoma, 11 with laryngeal malignancy and 20 involving hypopharynx. Among the participants buccal mucosa (n=22) was the most common subsite involved, majority (50%) had moderately differentiated squamous cell carcinoma and 53.4% presented in stage IV. 2 (2.6%) cases were positive for HPV consensus and both were positive for HPV 16, one case each in larynx and hypopharynx. There was statistical significance in the association between betel nut chewing, cigarette smoking and alcohol intake as risk factors in the carcinogenesis of HNSCC. Conclusion: In our setting in South India, HPV does not play a major role in the carcinogenesis of HNSCC but betel nut chewing, tobacco exposure and alcohol consumption remain major risk factors for HNSCC.