After renal transplantation, immunosuppressive regimens associated with high short-term survival rates are not necessarily associated with high long-term survival rates, suggesting that regimens may need to be optimized over time. Calcineurin inhibitor (CNI) withdrawal from a sirolimus-based immunosuppressive regimen may maximize the likelihood of long-term graft and patient survival by minimizing CNI-associated nephrotoxicity. In this study, a lifetime Markov model was created to compare the cost-effectiveness of a sirolimus-based CNI withdrawal regimen (sirolimus plus steroids) with other common CNI-containing regimens in adult de novo renal transplantation patients. Long-term graft survival was estimated by renal function and data from published studies and the US transplant registry, including short- and long-term outcomes, utility weights, and health-state costs were incorporated. Drug costs were based on average daily consumption and wholesale acquisition costs. The model suggests that treatment with sirolimus plus steroids is more efficacious and less costly than regimens consisting of a CNI, mycophenolate mofetil, and steroids; therefore, CNI withdrawal not only shows potential for long-term clinical benefits but also is expected to be cost-saving over a patient's life compared with the most commonly prescribed CNI-containing regimens