To investigate the role of plasminogen activator (PA) in cutaneous disease, we have used biochemical and immunocytochemical techniques to examine PA in normal and lesional skin. In normal human dermis, tissue PA is the predominant PA activity; however, in normal epidermis, urokinase type PA is the predominant PA activity. In contrast, PA activity in epidermis from lesions of patients with a variety of cutaneous diseases was predominantly tissue type enzyme with a much smaller contribution from urokinase. Our patient population included individuals with benign chronic pemphigus, pemphigus vulgaris, pemphigus foliaceous, bullous pemphigoid, or psoriasis. Using rabbit antibody specific for tissue type PA, we have immunocytochemically localized this enzyme in lesions from individuals with the above disorders. Our results indicate that tissue PA is consistently elevated in cutaneous lesions with diverse etiology, pathology, and clinical presentation.