Actinic cheilitis (AC) is a potentially malignant disorder, which can present degrees of epithelial dysplasia, and may even evolve into lip squamous cell carcinoma (LSCC). Since p63 is a protein homologous to p53, which can be associated with tumorigenesis in epithelial tissues, this study aims to evaluate it in AC and LSCC, in the hopes to estimate the biological behavior of these lesions. Forty AC lesions and sixty-five cases of LSCC were quantitatively analyzed by immunohistochemistry, using anti-p63 antibody with ten cases of normal lip mucosa used as a control group. In all AC and LSCC cases studied, it was possible to detect the presence of the p63 protein. There was no statistically significant difference between immunostained cells and degree of epithelial dysplasias, nor between the LSCC grading malignancy. Nevertheless, p63 immunoexpression showed to be significantly correlated with AC and LSCC lesions as compared to normal lip epithelium. The results indicate that p63 protein is consistently expressed in AC and LSCC, and might be of help in the differential diagnosis between normal and dysplastic/neoplastic epithelium, although the evaluation using a primary antibody to all isotypes did not prove to be a risk biomarker during lip carcinogenesis. Thus, the production of antibodies for the six different p63 isotypes is urged, since in isolation they can have predictive value, mainly the Delta Np63 isoforms.