Background A recent randomized phase III study of 719 de novo liver transplant recipients showed that early everolimus plus reduced-dose tacrolimus (EVR + rTAC) led to significantly better kidney function than standard TAC (TAC-C), without compromising efficacy. In that study, patients from North America (n = 211) had increased risk factors for posttransplant renal insufficiency at study start, relative to patients from Europe and rest of world (eg, worse renal function, more diabetes, older age). Methods A post hoc analysis was performed to assess whether these regional disparities affected study outcomes in North American patients. Results In this subpopulation, estimated glomerular filtration rates at randomization were higher in TAC-C over EVR + rTAC (76.4 vs 69.3 mL/min per 1.73 m2). Mean changes in estimated glomerular filtration rate values (mL/min per 1.73 m2) favored EVR + rTAC over TAC-C at months 12 (+3.7 vs-4.5; P = 0.032), 24 (+2.7 vs-6.6; P = 0.042), and 36 (+4.3 vs-8.1; P = 0.059). The composite efficacy endpoint of treated biopsy-proven acute rejection, graft loss, or death was 10.9%, 14.1%, and 14.1% for EVR + rTAC and 13.1%, 17.2%, and 19.3% for TAC-C at months 12, 24, and 36, respectively. Conclusions Although the North American cohort had more comorbidities, results were consistent with the overall population for efficacy and renal function.