Statement of the Problem: P63 gene is a member of TP53 and its homologous gene family. Its expression was observed in some odontogenic lesions, more expression in aggressive lesions.Purpose: This study aimed to investigate the possible diagnostic impact of P63 protein on dentigerous cysts and various types of ameloblastoma. Its expression with Ki-67 proliferation marker was also compared.Materials and Method: This cross-sectional retrospective study was enrolled on 25 cases of dentigerous cyst including 21 unicystic ameloblastomas and 17 conventional ameloblastomas. The expression of P63 and Ki-67 was assessed by immunohistochemical (IHC) examinations. Data were analyzed by employing Mann-Whitney and correlation coefficient tests.Results: P63 expression was significantly higher in ameloblastoma than unicystic ameloblastoma and dentigerous cysts. There was no significant difference between unicystic ameloblastoma and dentigerous cyst in P63 expression. A 90% cut-off point was obtained for basal layer which gave 88% sensitivity and 78% specificity to distinguish more invasive lesions from others. There was not any correlation between P63 and Ki-67 immunostaining in the three study groups.Conclusion: More aggressiveness and more invasiveness of odontogenic lesions depicted higher rate and also more intensive expression of P63. Moreover, the expression of P63 protein had not any correlation with Ki-67 protein in dentigerous cysts and ameloblastomas.