Cyclosporine (CsA) can induce prolonged tolerance to alloantigens, but it requires an intact thymus. In normal rats, CsA causes a rapid but reversible ablation of the thymic medulla with an associated loss of the Hassall's corpuscles and apparent maturation arrest of the thymocytes. We have tested the hypothesis that CsA induces a cell-mediated lysis of the medullary epithelium. Normal rats were treated with CsA (15 mg/kg) or vehicle. The thymocytes were then adoptively transferred into syngeneic target rats, purged of thymocytes by recent total-body irradiation. After 4-48 hr, the target animals were sacrificed. The target thymi showed increased lymphocytic exocytosis of the Hassall's corpuscles with OX-8+ (CD8+) T lymphocytes (OX-19+, OX-44+) and associated epithelial cell injury. Compared to recipients of control thymocytes, ultrastructural evaluation showed broad-based and point contact between lymphocytes and adjacent medullary epithelium with increased epithelial cell injury. The results support a cell-mediated injury to the Hassall's corpuscles in CsA-treated animals.