The aim of this study was to investigate a possible relation between oral squamous cell carcinoma (SCC), the presence of high‐risk human papillomavirus (HR‐HPV) DNA and p16 expression in young patients. Paraffin‐embedded tumor blocks from 47 oral SCC of young (≤40‐year old) patients were evaluated. The presence of HPV DNA in tumor specimens was analyzed by polymerase chain reaction (PCR) using GP5+/GP6+ generic primers (L1 region) followed by dot blot hybridization for HPV typing. When necessary, the HPV16 positivity was confirmed by PCR HPV16 E7‐specific primers. Cases involving young patients were compared with 67 oral SCC from patients ≥50‐year old (controls). Demographic and clinical data were collected to analyze patient outcomes. p16^ink4 expression was evaluated by immunostaining of tissue microarrays. HPV16 was detected in 22 (19.2%) cases; 15 (68.2%) young and 7 (31.8%) control patients, a statistically significant difference (p = 0.01). In 1 (1.7%) young group specimen, HPV DNA 16 and 18 was detected. p16 expression was observed in 11 (25.6%) cases from the young group and in 11 (19.6%) controls (p = 0.48). Association between HPV and p16 was verified, and it was statistically significant (p = 0.002). The higher prevalence of high‐risk HPV types, especially HPV16, may be a contributing factor to oral carcinogenesis in younger individuals.