We evaluated outcomes with the sirolimus (SRL) and mycophenolate mofetil (MMF) combination regimen (SRL/MMF) in solitary kidney transplant recipients transplanted between 2000 and 2005 reported to the Scientific Registry of Renal Transplant Recipients. Three-and-a-half percent received SRL/MMF (n = 2040). Six-month acute rejection rates were higher with SRL/MMF (SRL/MMF: 16.0% vs. other regimens: 11.2%, p < 0.001). Overall graft survival was significantly lower on SRL/MMF. SRL/MMF was associated with twice the hazard for graft loss (AHR = 2.0, 95% C.I., 1.8, 2.2) relative to TAC/MMF, also consistent in both living donor transplants (AHR = 2.4, 95% C.I., 1.9, 2.9) and expanded criteria donor transplants (AHR = 2.1, 95% C.I., 1.7-2.5). Among deceased donor transplants, DGF rates were higher in the SRL/MMF cohort (47% vs. 27%, p < 0.001). However, adjusted graft survival was also significantly inferior with SRL/MMF in DGF-free patients (AHR = 1.9, 95% C.I., 1.6-2.3). In analyses restricted to patients who remained on the discharge regimen at 6 months posttransplant, conditional graft survival in deceased donor transplants was significantly lower with SRL/MMF compared to patients on TAC/MMF or CsA/MMF regimens at 5 years posttransplant (64%, 78%, 78%, respectively, p = 0.001) and across all patient subgroups. In conclusion, SRL/MMF is associated with inferior renal transplant outcomes compared with other commonly used regimens.