This study evaluated 724 primary head and neck squamous cell carcinoma (HNSCC) in young and old patients, with regard to clinical profile and immunohistochemical expression of p53 protein. Associations among age, epidemiological and clinicopathological parameters, and survival analysis were evaluated. HNSCC in young people occurred in 14.5% (median age 40.7years; male-to-female ratio 5.9:1). A statistical association was demonstrated between age and family history of cancer, and between age and anatomical site. Among older patients, a higher presence of disease was noted in posterior sites. Expression of p53 was found in 71.7% of the samples and a higher expression was noted in lesions of young patients. Survival analysis showed that the age parameter is not a reliable prognostic factor for HNSCC. Among young patients, cervical metastasis was associated with worse survival. The presence of a family history of cancer in young patients could indicate genetic susceptibility and molecular disturbances in the p53 pathway in HNSCC of young and older patients seem to be distinct.