Recipients of solitary liver and kidney transplants are living longer, and this increases their risk of long-term complications such as recurrent hepatitis C virus (HCV) and drug-induced nephrotoxicity. These complications may require retransplantation. Since the adoption of the Model for End-Stage Liver Disease, the number of simultaneous liver-kidney transplantation (SLK) procedures has increased. However, there are no standardized criteria for organ allocation to SLK candidates. The aims of this study were to retrospectively compare recipient and graft survival with liver transplantation alone (LTA), SLK, kidney after liver transplantation (KALT), and liver after kidney transplantation (LAKT) and to identify independent risk factors affecting recipient and graft survival. The United Network for Organ Sharing/Organ Procurement and Transplantation Network database (1988-2007) was queried for adult LTA (66,026), SLK (2327), KALT (1738), and LAKT procedures (242). After adjustments for potential confounding demographic and clinical variables, there was no difference in recipient mortality rates with LTA and SLK (P = 0.02). However, there was a 15% decreased risk of graft loss with SLK versus LTA (hazard ratio = 0.85, P < 0.001). The recipient and graft survival rates with SLK were higher than the rates with both KALT (P <0.001 and P <0.001) and LAKT (P = 0.003 and P < 0.001). The following were all identified as independent negative predictors of recipient mortality and graft loss: recipient age ≥ 65 years, male sex, black race, HCV/diabetes mellitus status, donor age ≥ 60 years, serum creatinine level ≥2.0 mg/dL, cold ischemia time > 12 hours, and warm ischemia time > 60 minutes. Although the recent increase in the number of SLK procedures performed each year has effectively decreased the number of potential donor kidneys available to patients with end-stage renal disease (ESRD) awaiting kidney transplantation, SLK in patients with end-stage liver disease and ESRD is justified because of the lower risk of graft loss with SLK versus LTA as well as the superior recipient and graft survival with SLK versus serial liver-kidney transplantation. Liver Transpl, 2012. © 2012 AASLD.