Transforming growth factor-alpha (TGF-alpha) is a potent mitogen for epithelial cells that bas been localized to normal human appendageal epithelia To further understand the role of TGF-alpha in human appendages, we examined TGF-alpha-expression immunohistochemically in 17 types of human appendageal tumors differentiating toward hair follicles, eccrine, apocrine, and sebaceous glands. In order of decreasing degrees of differentiation, tumors could be divided into hyperplasias, adenomas, benign epitheliomas; and primordial epitheliomas. Using an antibody that recognizes primarily the 6-kd and 13 -kd forms of TGF-alpha, TGF-alpha-immunostaining in 16 of 17 tumor types analyzed was found to follow a similar pattern, with expression in hyperplasias > adenomas > benign epitheliomas > primordial epitheliomas. Within a given tumor TGF-alpha expression also correlated well with the known differentiation state of the tumor cell types. The results suggest that TGF-alpha-expression is directly correlated with the differentiation state of hair follicle, eccrine, apocrine and sebaceous tumors in human skin, and raises the possibility that TGF-alpha may play a role in the differentiation of appendageal epithelia.