A highly selected subject group comprising pediatric recipients of liver (n = 36) and small intestine alone (n = 1) or multivisceral graft (n = 2) were converted to sirolimus maintenance therapy for tacrolimus-related side effects (n = 32) or by primary intent (n = 7). Indications were nephrotoxicity (n = 14), primary intent (n = 7), post-transplant lymphoproliferative disorder (n = 6), seizures (n = 4), recurrent acute rejection (n = 2), and cardiomyopathy (n = 1). Thirty subjects (78%) experienced successful conversion, with one subject requiring atorvastatin for hypercholesterolemia and hypertriglyceridemia. Nine subjects (22%) were converted back to tacrolimus for serious adverse events including acute rejection (n = 2), elevated liver function tests (n = 1), severe leucopenia (n = 1), non-compliance (n = 2), recurrent malignancy/death (n = 1), steatohepatitis (n = 1), and thrombocytopenic thrombotic purpura (n = 1). Among subjects with nephrotoxicity, significant benefit was seen only in those subjects with shorter time to rescue after transplantation (n = 8 of 14 subjects). Additional benefits included a significant decrease in mean serum creatinine from pretransplant values for the entire population, and elimination of antihypertensive treatment in all five subjects receiving it prior to conversion. Hemoglobin, serum cholesterol and triglycerides, white cell counts and platelets remained within normal limits for the duration of follow-up (36 month). Conversion from tacrolimus to sirolimus is successful in selected pediatric liver and intestine recipients. Chronic nephrotoxicity may be ameliorated by early conversion. Improvement in renal function and hypertension management, and absence of sirolimus-related adverse events argue for prospective evaluation of regimens in which mTOR inhibitors are used without calcineurin inhibitors in children.