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Background: Histopathologic distinction between keratoacanthoma (KA) and squamous cell carcinoma (SCC) is challenging. We surmised that a discriminatory immunostain would be clinically meaningful. Previous investigators have found CD123-positive plasmacytoid dendritic cells (PDCs) are more prominent in KA than SCC. We sought to determine if CD123 immunostaining might have value as a diagnostic test for distinguishing KA from SCC., Methods: We used blinded, semi-automated image analysis to compare CD123 expression in 66 KAs and 63 SCCs in a tissue microarray., Results: PDCs were present in both KA and SCC. Mean PDC frequency was higher in KA than SCC (14.2 vs 11.2 mean cells/0.0945 square mm) but the difference was not statistically significant (P = 0.1240). There was no significant difference in mean PDC cluster frequency, mean intratumoral PDC frequency, or the percentage of PDCs as proportion of the total mononuclear inflammatory cell infiltrate between KA and SCC., Conclusion: CD123 immunostaining is not a clinically useful test for distinguishing KA from SCC., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)