The expression of cyclooxygenase-2 (COX-2) and Keratin-15 (K15) in radicular cysts (RCs) is poorly understood. Identifying the expression of these two markers may modify the current treatment of RC. The objective of this study was to evaluate the expression of COX-2 and its relationship to K15 expression in the odontogenic epithelial cells of the RC.A total of 18 RCs were immunohistochemically analyzed for COX-2 and K15 expression. The cellular inflammatory reaction in the cyst wall was also assessed by measuring the percentage of inflammatory cells to the total number of cells.COX-2 expression in the odontogenic epithelium of RC was absent in 11.1 % (n=2), mild in 27.8 % (n=5), moderate in 22.2% (n=4) and strong in 38.9% (n=7). Meanwhile, K15 expression was absent in 27.8% (n=5), mild in 16.7% (n=3), moderate in 44.4% (n=8), and strong in 11.1% (n=2) of the cases. The inflammatory infiltrate was mild in 2 cases (11.1%), moderate in 6 cases (33.3%), and high in 10 cases (55.6%). Spearman's correlation test revealed significant correlation (rho= .533; p= .023) between COX-2 and K15 expression in the odontogenic epithelium of RC. However, no correlation was noted between inflammation and expression of COX-2 (rho= 0.248, p=.321) or K15 (rho= -0.162, p= .520).There is high and correlated expression of COX-2 and K15 in the odontogenic epithelium of RC. COX-2 could therefore be involved in epithelial cell differentiation of the cyst. Additionally, the expression of K15 in RC may be an indicator of epithelial cell differentiation. Key words:Cyclooxygenase, COX-2, Keratin-15, K15, Radicular cyst.Copyright: © 2022 Medicina Oral S.L.