Squamous cell carcinoma (SCC) and keratoacanthoma (KA) are skin neoplasms of epithelial origin. In contrast to clearly malignant skin neoplasm SCC, KA is an unusual cutaneous neoplasm with a tendency to regression. The distinction between these two neoplasms, on histological grounds only, is still a challenge. In order to investigate further and to assess the possible differences in transforming growth factor-alpha (TGF-alpha) expression between SCC and KA, 40 of skin tumor specimens, 20 cases of each SCC and KA were analyzed immunohystochemicaly. We have found a significant difference in staining patterns between KA and SCC. In KAs we have detected TGF-alpha staining mainly diffusely (90% of cases) and without peripheral staining of cells in 1-2 layers (60% of cases). Contrary, there was a mostly patchy staining (55% of cases) with peripheral staining of cells in 1-2 layers (100% of cases) in SCCs. Generally, differentiation between KA and SCC can be based on clinical and histological ground, but the distinction between these two skin tumors could sometimes be difficult. We have shown that these skin neoplasms could be differentiated based on staining patterns of TGF-alpha expression, thus this method could aid in differentiation between these two closely related entities in clinical practice.