AIM: To examine whether the reversibility of chronic cyclosporine A (CsA) nephrotoxicity is associated with apoptotic cell death and its regulatory factors. METHODS: Chronic CsA nephrotoxicity was induced in Sprague- Dawley rats by administering CsA (15 mg/kg, sc) for 5 weeks, and then withdrawing it for 5 or 10 weeks. The effect of CsA withdrawal on apoptotic cell death was evaluated by an in situ TdT-mediated deoxyuridine triphos- phate-biotin nick end-labeling (TUNEL) assay and the expression of pro-apoptotic [(transforming growth factor- beta1 (TGF-β1) and Fas] and anti-apoptotic [epidermal growth factors (EGF) and Bcl-2] factors. RESULTS: Discontinuation of CsA induced significant decreases in TUNEL-positive cells in a time-dependent manner and the reduction in TUNEL-positive cells was correlated with the tubulointerstitial fibrosis score (r=0.919, P<0.01). Upregulation of TGF-β1 and Fas expression in CsA-treated rat kidneys was decreased significantly after with- drawal of CsA. In contrast, downregulated EGF and Bcl-2 expression returned to normal or supernormal levels. CONCLUSION: CsA withdrawal is associated with a decrease in apoptotic cell death and with changes in the expression of pro-apoptotic and anti-apoptotic molecules involved in renal wound repair. This may constitute one of the mechanisms underlying the reversibility of chronic CsA nephrotoxicity. METHODS: Chronic CsA nephrotoxicity was induced in Sprague-Dawley rats by administered CsA (15 mg / kg, sc) for 5 weeks, and then withdrawing it for 5 or 10 weeks. The effect of CsA withdrawal on apoptotic cell death was evaluated by an in situ TdT-mediated deoxyuridine triphos-phate-biotin nick end-labeling (TUNEL) assay and the expression of pro RESULTS: Discontinuation of CsA induced significant decrease in TUNEL-positive cells in a time-dependent manner and the reduction in TUNEL-positive cells were correlated with the tubulointerstitial fibrosis score (r = 0.919, P <0.01). Upregulation of TGF-β1 and Fas expression in CsA-treated rat kidneys was decreased significantly with with- drawa l of CsA. In contrast, downregulated EGF and Bcl-2 expression returned to normal or supernormal levels. CONCLUSION: CsA withdrawal is associated with a decrease in apoptotic cell death with changes in the expression of pro-apoptotic and anti-apoptotic molecules involved in renal wound repair. This may constitute one of the mechanisms underlying the reversibility of chronic CsA nephrotoxicity.