Background: Chronic cyclosporine nephrotoxicity (CCN) after heart transplantation is a progressive condition that may lead to end-stage renal failure. The extent to which CCN is reversible with reduction or withdrawal of cyclosporine therapy is unknown. The aim of this study was to assess the reversibility of CCN and to assess the safety and efficacy of a strategy of cyclosporine dosage reduction, combined with conversion from azathioprine to mycophenolate mofetil (AZA/MMF switch) to maintain immunosuppression. Methods: An AZA/MMF switch followed by cyclosporine dose reduction was undertaken in 30 heart transplant recipients (23 men, 7 women; mean age, 54 ± 2 years) with established CCN at a mean of 90 ± 9 months after transplantation (range, 17-182 months). The mean maintenance MMF dosage was 2.3 ± 0.1 g/day (n = 28). Mean cyclosporine dosage was decreased from 2.3 ± 0.2 mg/kg/day before AZA/MMF switch to 1.6 ± 0.2 mg/kg/day. Results: Three patients (10%) were withdrawn from MMF, 2 because of diarrhea and the third because of severe pneumonia that developed within 2 weeks of AZA/MMF switch. All 3 were restabilized with AZA. One patient (4%) experienced acute rejection 7 months after AZA/MMF switch. This resolved after an oral pulse of prednisolone. Systemic infections occurred in 6 patients within 12 months of AZA/MMF switch. Actuarial survival 1 year after AZA/MMF switch was 86% ± 6%. One patient died of infection and 3 of other causes. Serum creatinine concentration decreased from 248 ± 15 μmol/liter before cyclosporine dosage reduction to 193 ± 11 μmol/liter and 206 ± 19 μmol/liter at 3 and 12 months after dosage reduction (both p < 0.01 versus baseline, n = 23). Of the 23 patients who remained on MMF at 12 months, a decrease in serum creatinine was documented in 19 (83%). Four patients showed no improvement or showed deterioration in renal function, and three of these progressed to end-stage renal failure. Conclusions: Chronic cyclosporine nephrotoxicity has a significant reversible component in most patients. A strategy of AZA/MMF switch combined with cyclosporine dosage reduction is generally well tolerated and results in short-term improvement in renal function in most patients. Close vigilance is required during the first 12 months after AZA/MMF switch because both acute rejection and infection may occur.