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Tobacco and alcohol consumption are considered the main risk factors for oral squamous cell carcinoma (OSCC); however, the role of these factors in patients younger than 40 years is controversial, so it has been suggested that genomic instability and high-risk human papillomavirus (HR-HPV) infection may be contributing factors to oral carcinogenesis at a young age. Therefore, the aim of this study was to evaluate the immunoexpression of cell cycle proteins according HPV status in OSCC affecting young patients.A tissue microarray construction based on 34 OSCC samples from young patients (<40 years old) was subjected to immunohistochemical reactions for Ki67, cyclin D1, C-ErbB2, p21, Myc, epidermal growth factor receptor, p53, and p16 antibodies.The clinicopathologic features and the immunoexpression of all tested proteins were similar in both groups. Patients with HPV-related OSSC tended to have better cancer-specific survival (CSS; 39% vs 60% 5-y CSS), and overall survival (OS; 29.2% vs 60% 5-year OS). However, this difference was not statistically significant.No significant difference exists in the expression of cell cycle proteins studied between HR-HPV DNA–positive and HR-HPV DNA–negative OSCC affecting young patients.