Keratoacanthoma (KA) and squamous cell carcinoma (SCC) are two cutaneous conditions with morphological resemblance, which can complicate the diagnosis in some cases. Using immunohistochemistry staining of biomarkers could be beneficial in resolving this obstacle.We investigated a variety of biomarkers assessed in different studies in order to find the most important and helpful biomarkers for differentiation between SCC and lesions capable of spontaneous regression.MEDLINE via PubMed and Google Scholar database were used to identify relevant literature up to 15 June 2022. The aim of our analyses was to determine the capability of biomarkers to distinguish between SCC and lesions capable of spontaneous regression using calculated individual and pooled odds ratios (OR) and 95% confidence intervals (CI) and I2 tests.Six potential biomarkers were CD10 with pooled OR= 0.006 (95% CI: 0.001-0.057) and I2=0%; COX-2 with pooled OR=0.089 (95% CI: 0.029-0.269) and I2=17.1%; elastic fibers with pooled OR= 6.69 (95% CI: 2.928-15.281) and I2=0%; IMP-3 with pooled OR=0.145 (95% CI: 0.021-1.001) and I2=44.5%; P53 with pooled OR=0.371 (95% CI: 0.188-0.733) and I2=55.9%; AT1R with OR=0.026 (95% CI: 0.006-0.107).We suggest the utilization of the following IHC biomarkers for discrimination between lesions with spontaneous regression such as KA and SCC: CD10, COX-2, and elastic fibers.