Aims: To evaluate the clinicopathological significance of p16 expression in the surgical management of squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx, and larynx. Method: p16 expression in 225 head and neck squamous cell carcinomas (HNSCCs) was studied using an immunohistochemical method and paraffin wax embedded tumour tissues. Associations between p16 expression and clinicopathological features were investigated. Results: Decreased p16 expression was found in 48% of the tumours. There was a higher frequency of decreased p16 expression in tumours of the larynx compared with those from the pharynx and oral cavity. There was a significant correlation between decreased p16 expression and more advanced T stage. There was no significant correlation between p16 expression and sex, age, tumour grade, nodal metastasis, recurrence, or survival. Conclusion: There was a high frequency of downregulation of p16 expression in HNSCC. Tumours of the larynx had a significantly higher frequency of weak p16 expression compared with tumours of the oral cavity and pharynx. Downregulation of p16 contributed to cellular proliferation, resulting locally in a more advanced tumour. It had no prognostic significance for nodal metastasis and survival.