Background <p>Squamous cell carcinoma is the most common type of head and neck cancer. A subset of head and neck squamous cell carcinoma (HNSCC) is caused by human papillomavirus (HPV). Data regarding HPV-driven HNSCC from low- and middle-income countries is lacking.</p> Methods <p>A cross-sectional multicentre study of adult patients diagnosed with primary HNSCC between 2016 and 2020 was carried out. HPV status was determined through detection of high-risk HPV mRNA via in situ hybridization (RNAISH). Tumours were classified as being HPV-driven when there was positivity for RNAISH. p16^INK4a immunohistochemistry (IHC) and HPV DNA detection and genotyping (HPVDNA) via a PCR-based method were also carried out. The prognostic utility of RNAISH, p16^INK4a immunohistochemistry (IHC) alone and combined p16^INK4a &amp; HPVDNA were assessed using survival analysis.</p> Results <p>A total of 356 cases of HNSCC were assessed for HPV status. Median age was 64 years (IQR: 15), and 69.9% of patients were males. The prevalence of HPV-driven HNSCC was approximately 11.0% (95% CI: 7.9–14.7%). The vast majority of HPV-driven HNSCC were from the oropharynx (94.9%). None of the tumours originating from the oral cavity, larynx and hypopharynx were HPV-driven. Seven different genotypes were found in HPV-driven HNSCC.</p> Conclusions <p>In our cohort, HPV-driven HNSCC was primarily encountered in tumours originating from the oropharynx. HPV16 was the most frequently encountered genotype in our cohort. It is recommended that determination of HPV status be based on single testing with RNAISH or dual testing of p16^INK4a IHC in conjunction with HPVDNA as an acceptable alternative in resource limited settings to improve patient stratification for treatment as well as clinical outcomes.</p>