Seborrheic keratoses were investigated by means of histo- and biochemical techniques in order to define the epidermal differentiation and proliferation of this most common epithelial tumor in adults. The following markers have been used in our study: cytokeratins, epidermal proteins binding zinc, insulin receptors, tissue plasminogen activator (tPA), as well as calmodulin (immunohistochemical and quantitative evaluation). Immunohistochemical investigation of seborrheic keratoses revealed a decreased tPA expression; their epidermal concentration of calmodulin was doubled. The differentiation markers failed to show any significant deviation from normal skin. Thus, seborrheic keratoses are associated with normal epidermal differentiation in spite of morphogenic alterations. Pathogenetically, we have to consider epidermaldermal interactions.