Nephrotoxicity is an adverse effect of cyclosporine and tacrolimus. Studies comparing their long-term nephrotoxicities are lacking. This study evaluates the nephrotoxicity of these agents over a 7-year period following heart transplantation. Pediatric heart-transplant recipients receiving cyclosporine or tacrolimus as primary immunosuppression were evaluated at two centers from 1982 to 1998. Data collected included serum creatinine, height and weight prior to transplantation, at 1 and 6 months and 1 years post transplantation, and at yearly intervals thereafter. Creatinine clearance was calculated and compared between the two groups. Glomerular filtration rate was measured using Tc-99m diethylenetriaminepentacetic acid. In total, 123 patients were evaluated. Demographic data of the two groups were comparable. Creatinine clearance demonstrated a steady decline. This decline did not differ statistically between the two groups: tacrolimus 98.9 and 90.7mL/min/1.73 m2 at 1 month and 5 years, respectively; cyclosporine 110.7 and 81.7 mL/min/ 1.73 m2 at 1 month and 5 years, respectively. Four patients developed end-stage renal failure. Calculated creatinine clearance consistently overestimated glomerular filtration rate, the latter being greater than 2 standard deviations below the mean normal in 38% of patients. We conclude that the nephrotoxicities of tacrolimus and cyclosporine are comparable over the medium- to long-term in pediatric heart-transplant recipients.