Background: Modern immunosuppression protocols for renal transplantation balance the risks of over-immunosuppression, namely infection and drug toxicity, against the risk of rejection. There is limited literature for the optimization of immunosuppression by risk-stratification according to patient risk factors for rejection in renal transplantation. The aim of this study is to evaluate the degree of adherence to a newly implemented risk-stratified protocol. Methods: This is a retrospective single center study of the immunosuppression orders ordered for adult solitary kidney transplants during the risk-stratified (RS) protocol period from 2012 to 2013. Risk-stratification was based on immunological risk (sensitization and age) with total rabbit antithymocyte globulin (ATG) dosing ranging from 1.5 to 6 mg/kg to target an absolute lymphocyte count of less than 100 cells/μL. Results: 53 patients underwent renal transplantation during the RS period. Patient survival was 100% with 98% graft survival. During the initial transplant encounter, 81% of patients received the appropriately risk-stratified dose of ATG with the most common reason for protocol deviation being patients stratified to the incorrect level of immunologic risk. Of the ATG deviations, 50% of patients were dosed below protocol due to infection concerns and 50% were dosed above protocol due to rejection concerns. More than half (56%) of the patients who received an off-protocol dose of ATG were transplanted within the first 3 months of the protocol change. At discharge, the majority of patients were sent home on the protocol doses of prednisone and mycophenolate mofetil (76.9% and 71.7%, respectively). Slightly more than half of the patients were discharged on a dose of tacrolimus equaling 0.05 mg/kg twice daily or greater (52.9%), but the majority of patients had the per protocol-driven tacrolimus goal trough levels at discharge (88.2%). At one month post-transplantation, less than one-third (28%) of patients had tacrolimus trough levels within the designated trough levels. Conclusions: Despite an initial learning curve in the transition period, the implementation of a risk stratified immunosuppression protocol was successful and should translate to decreased infectious complications and excellent outcomes. Outpatient dosing and monitoring of tacrolimus may require further optimization to reach goal levels.