Keratoacanthomas are rapidly growing benign epithelial derived neoplasms that may evolve into squamous cell carcinomas, or represent a variant of squamous cell carcinoma. ICAM (CD-54) is a ligand for the cell adhesion receptor LFA-1, shown to be important in immune stimulation that is upgraded in inflammatory cutaneous disorders. VCAM (CD-106) is an adhesion molecule normally found in stimulated endothelium, that plays a critical role in the migration of leukocytes. We examined the immunohistochemical expression of ICAM (CD-54) and VCAM (CD-106) in a series of 50 evolving, fully developed, resolving keratoacanthoma and well-differentiated and poorly differentiated squamous cell carcinoma to evaluate the possible temporal and pathogenic relation of these immune recognition markers and epithelial derived tumors. ICAM (CD-54) showed an increase in expression in the fully developed keratoacanthoma and was absent in the evolving and resolved keratoacanthoma. In the squamous cell carcinomas, expression was focally observed in the well-differentiated squamous cell carcinomas with a dramatic increase seen in the poorly differentiated squamous cell carcinomas. Similarly, VCAM (CD-106) was expressed in the fully developed keratoacanthoma and was absent in the evolving and resolved keratoacanthoma. Moderate expression for VCAM (CD-106) was seen in the well-differentiated squamous cell carcinoma, and intense expression was seen in the fully developed keratoacanthoma and poorly differentiated squamous cell carcinoma. As a group, keratoacanthoma and squamous cell carcinoma are immunophenotypically distinct. There is a temporal related increase in expression of VCAM (CD-106) in conjunction with the evolution of keratoacanthoma. Increased expression of both markers is seen with squamous cell carcinoma dedifferentiation. Application of these markers might be an important adjunct in predicting the biologic behavior and pathogenesis of these lesions.