Abstract Background Human papillomavirus (HPV)‐driven head/neck squamous cell carcinomas (HNSCC) prevalence varies globally. We evaluated HPV DNA and p16 INK4a in formalin fixed paraffin embedded (FFPE) HNSCC from Argentina, Brazil, Colombia, and Peru. Methods HPV was genotyped by PCR‐hybridization. All HPV DNA positive and some HPV DNA negative cases underwent p16 INK4a immunohistochemistry. Results HPV DNA was detected in 32.8%, 11.1%, and 17.8% of oropharyngeal (OPC), oral cavity (OCC) and laryngeal (LC) cancers, respectively. OPC HPV prevalence was higher in Colombia (94.7%), and Argentina (42.6%) compared to Brazil (10.6%) and Peru (0.0%). HPV‐16 was the most detected. Other HPVs were found in LC. Higher rates of p16 INK4a positivity were observed among HPV positive OPC/OCC cases compared to LC cases. Conclusions Our results support a role for HPV‐16 in a subset of HNSCC, corroborate the heterogeneity observed in samples from different countries, and contribute additional etiological and biomarkers information in tumors of significant impact worldwide.