Because calcineurin inhibitor (CNI)-induced nephrotoxicity contributes significantly to late renal allograft loss, sirolimus (SRL)-based, CNI-free maintenance immunosuppression has been advocated, but data in the pediatric population are scarce. We therefore analyzed the efficacy and safety of an SRL-based immunosuppressive regimen plus mycophenolate mofetil (MMF) and corticosteroids vs. CNI minimization (mean dose reduction by 39%) plus MMF and corticosteroids in 19 pediatric recipients with biopsy-proven CNI-induced nephrotoxicity in a single-center case–control study. In the SRL group, we observed, one yr after study entry, an improvement of glomerular filtration rate (GFR) by 10.3 ± 3.0 mL/min/1.73 m2 (p < 0.05 vs. baseline) in seven of 10 patients and a stabilization in the remaining three, while in the CNI minimization group GFR improved by 17.7 ± 7.1 mL/min/1.73 m2 (p < 0.05) in six of nine recipients and stabilized in the remaining three. No patient in either group experienced an acute rejection episode. The main adverse event under SRL therapy was a transient hyperlipidemia in 70% of patients. In pediatric renal transplant recipients with declining graft function because of CNI-induced nephrotoxicity, CNI withdrawal and switch to SRL-based therapy or CNI minimization are associated with a comparable improvement of GFR after 12 months of observation.