Calcifying odontogenic cyst (COC) is a developmental odontogenic cyst in the jaw. Because of its diverse histopathologic features and biological behavior, there has long been confusion with regard to its nature as a cyst or neoplasm. This study evaluated the proliferative activity of 57 COC samples, including simple cyst (10 cases), cystic neoplasm (34 cases), solid neoplasm (6 cases) and combined lesion (7 cases) by p53 and PCNA immunohistochemical staining. For assessment of p53 and PCNA positivity, the number of positively stained cells with brown-stained nuclei was counted in 1000 cells from each sample. p53 and PCNA expression in the solid neoplasm subtype were significantly higher when compared to cystic neoplasm and simple cyst (P < 0.05). The lowest p53 and PCNA expression was found in the simple cyst subtype. p53 and PCNA expression in the basal and suprabasal layers was significantly higher in the solid subtype when compared to others, and the difference between COC groups was significant. The results demonstrated that within benign types of COC, the amount of p53 and PCNA in proliferative epithelium is significantly higher when compared to non-proliferative epithelium. p53 and PCNA markers are possible parameters for differentiation of COC subtypes.