Abstract Background: Keratoacanthoma (KA) is a common, unique benign keratinocytic neoplasm, that mostly develops within 6-8 weeks, with spontaneous regression after 3-6 months and shares features with squamous cell carcinomas (SCCs). It is critical to recognize these neoplasms since they exhibit mark-edly distinct clinical characteristics. There are no criteria that are sensitive enough to discriminate reliably between KA and SCC. The purpose of this research is to determine the possible role of COX2 and CD10 in the distinction of KA and SCC. Material and Methods: This is a retrospective, controlled, selected study conducted on paraffin blocks including: 20 cases of squamous cell carcinoma, Twelve cases of keratoa-canthoma and five cases of normal skin tissue as control from plastic surgery. Cases were retrieved from the histopathologic archives of the Pathology Department, Faculty of Medicine, Benha University, between 2016 and 2019. Immunohistochem-ical staining for CD10 and COX2 was performed and the pattern of expression was examined, analyzed, correlated with clinicopathologic data and statistically studied. Results: Expression of CD10 was almost absent in the stromal component of KA cases (91.7%) while its expression in the stromal component of SCC was in all cases (100%) with statistically highly significant difference (p < 0.001). Expression of COX2 was within 50% of KA cases while in SCC, it was expresses in 95% examined cases with a significant statistical correlation (p < 0.005). Conclusion: The current research shown that CD10 and COX-2 may be useful in diffrentiating keratoacanthomas from squamous cell carcinoma.