Immunohistochemically detectable levels of p53 may be seen early in the malignant transformation of some neoplasms. To determine if p53 is immunocytochemically detectable, and therefore presumptively abnormal, in oral dysplasias and in situ carcinomas, and to explore the natural history of p53 protein expression in these lesions, sequential biopsies from patients with lesions occurring in the same anatomic site were examined. Formalin‐fixed, paraffin‐embedded sections from 19 patients were evaluated immunohistochemically for p53 protein using antibody clones Pab1801 and BP53‐12. With two exceptions, comparable results were observed with these antibodies. p53 protein was detected immunocytochemically in 6 of 13 patients with dysplasias; 3 of these progressed to p53‐positive invasive carcinoma, one advanced to a more severe grade of p53‐positive dysplasia, one developed into a p53‐negative verrucous carcinoma, and one represented a p53‐positive dysplasia developing five years after treatment of a p53‐positive carcinoma. The p53‐positive dysplasias, which were found in all subtypes (mild, moderate, severe), preceded histologic malignant change by months to years. p53 detection was evident in 4 of 6 patients with in situ lesions. Sequential biopsies of three of these lesions showed no change in lesion histology or p53 staining, and one lesion advanced to a p53‐positive carcinoma. It is concluded that p53 protein may be detected early in the development of a subset of p53‐positive oral squamous cell carcinomas. This phenomenon may be seen in dysplasias and in situ lesions, and it may have pr