Maintenance immunosuppression with calcineurin inhibitors (CNIs) following renal transplantation is associated with nephrotoxicity and accelerated graft loss. We aimed to assess whether conversion to sirolimus-based immunosuppression would affect the progression of renal impairment. In this single center, randomized controlled trial, 40 renal transplant recipients between 6 months and 8 years post-transplant were randomly assigned to remain on their CNI (cyclosporin or tacrolimus) or to switch to sirolimus. The primary outcome measure was change in glomerular filtration rate (GFR) measurement at 12 months. Analysis was by intention-to-treat. Of the 40 patients randomized, 2 patients never took the study drugs and were excluded, leaving 19 patients per group. There was a significant change in GFR at 12 months following conversion to sirolimus (12.9 mL/min, 95% CI 6.1-19.7; p < 0.001). Following conversion, the principal adverse events were the development of rashes (68%), particularly acne, and mouth ulcers (32%). No patient in either group experienced an acute rejection episode. In renal transplant recipients, a change in maintenance therapy from CNIs to sirolimus is associated with significant improvement in GFR at 12 months.