Major Histocompatibility Complex (MHC) class II-positive cells are almost completely absent in the rat thymic medulla after cyclosporin A (CsA) exposure. This phenomenon has been related to alterations in the medullary interdigitating cells (IDCs), representing either down-modulation of RT1 class II antigen on persistent IDCs, or actual disappearance of IDCs. To resolve this issue, we performed an ultrastructural study of the rat thymic medulla during CsA treatment (15 mg/kg body weight/day CsA subcutaneously for 7 to 14 days). At day 7 after exposure, only very few IDCs could be identified. They showed an abnormal ultrastructural morphology as judged by inconspicuous membrane interdigitations and lack of Birbeck granules. At day 14, the number of IDCs was larger. At this time, the IDCs had a normal ultrastructure, except for the almost complete absence of Birbeck granules. We conclude that CsA causes an initial depletion of IDCs from the thymic medulla. The ultrastructural morphology of the few IDCs present suggests an immature character. New IDC immigrants appear in the medullary area already during CsA treatment, indicating early recovery.