The authors recently demonstrated that cyclosporine (CsA) treatment of mice caused a remarkable reduction of L3T4+Lyt-2- subset in the thymocytes as well as the striking decrease in the size and cellularity of the thymic medulla. To elucidate the underlying mechanism of such thymic alterations, an immunohistochemical study on the thymic epithelial cells was made in mice receiving CsA. In the medulla, a marked reduction of Ia-positive, keratin positive and Ulex europeus agglutinin 1 (UEA 1) binding epithelial cells was observed. CsA also induced a reduction of anti-keratin stainability of cortical epithelial cells and of Ia antigen expression by them. The results of this study indicate that CsA is not only directly impair thymocyte function but also may act on epithelial cells in the thymus. It is suggestive that CsA may affect T cell differentiation and maturation via alteration of Ia-positive thymic epithelial cells.