More candidates with creatinine levels ≥ 2 mg/dL have undergone liver transplantation (LT) since the implementation of Model for End-Stage Liver Disease (MELD)–based allocation. These candidates have higher posttransplant mortality. This study examined the effect of serum creatinine on survival benefit among candidates undergoing LT. Scientific Registry of Transplant Recipients data were analyzed for adult LT candidates listed between September 2001 and December 2006 (n = 38,899). The effect of serum creatinine on survival benefit (contrast between waitlist and post-LT mortality rates) was assessed by sequential stratification, an extension of Cox regression. At the same MELD score, serum creatinine was inversely associated with survival benefit within certain defined MELD categories. The survival benefit significantly decreased as creatinine increased for candidates with MELD scores of 15 to 17 or 24 to 40 at LT (MELD scores of 15-17, P < 0.0001; MELD scores of 24-40, P = 0.04). Renal replacement therapy at LT was also associated with significantly decreased LT benefit for patients with MELD scores of 21 to 23 (P = 0.04) or 24 to 26 (P = 0.01). In conclusion, serum creatinine at LT significantly affects survival benefit for patients with MELD scores of 15 to 17 or 24 to 40. Given the same MELD score, patients with higher creatinine levels receive less benefit on average, and the relative ranking of a large number of wait-listed candidates with MELD scores of 15 to 17 or 24 to 40 would be markedly affected if these findings were incorporated into the allocation policy. Liver Transpl 15:1808–1813, 2009. © 2009 AASLD.