Incompatible live donor kidney transplantation (ILDKT) offers a survival advantage over dialysis to patients with anti-HLA donor-specific antibody (DSA). Program-specific reports (PSRs) fail to account for ILDKT, placing this practice at regulatory risk. We collected DSA data, categorized as positive Luminex, negative flow crossmatch (PLNF) (n-=-185), positive flow, negative cytotoxic crossmatch (PFNC) (n-=-536) or positive cytotoxic crossmatch (PCC) (n-=-304), from 22 centers. We tested associations between DSA, graft loss and mortality after adjusting for PSR model factors, using 9669 compatible patients as a comparison. PLNF patients had similar graft loss; however, PFNC (adjusted hazard ratio [aHR]-=-1.64, 95% confidence interval [CI]: 1.15-2.23, p-=-0.007) and PCC (aHR-=-5.01, 95% CI: 3.71-6.77, p-<-0.001) were associated with increased graft loss in the first year. PLNF patients had similar mortality; however, PFNC (aHR-=-2.04; 95% CI: 1.28-3.26; p-=-0.003) and PCC (aHR-=-4.59; 95% CI: 2.98-7.07; p-<-0.001) were associated with increased mortality. We simulated Centers for Medicare & Medicaid Services flagging to examine ILDKT's effect on the risk of being flagged. Compared to equal-quality centers performing no ILDKT, centers performing 5%, 10% or 20% PFNC had a 1.19-, 1.33- and 1.73-fold higher odds of being flagged. Centers performing 5%, 10% or 20% PCC had a 2.22-, 4.09- and 10.72-fold higher odds. Failure to account for ILDKT's increased risk places centers providing this life-saving treatment in jeopardy of regulatory intervention. In this 22-center study of HLA-incompatible live donor kidney transplants (ILDKT), the authors demonstrate the increased risk of graft loss and death associated with increasing anti-HLA donor-specific antibody strength, and they quantify the significantly increased risk of flagging for regulatory scrutiny by the Centers for Medicare & Medicaid Studies that is incurred by centers that perform ILDKT. See editorial by Cole and Tinckam on page 1475. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.