BACKGROUND: Widespread implementation of ABO-incompatible (ABOi) living donor kidney transplantation (LDKT) has been proposed as a means to partially ameliorate the national shortage of deceased donor kidneys. Acceptance of this practice has been encouraged by reports from experienced centers demonstrating acute rejection (AR) rates similar to those obtained with ABO-compatible (ABOc) LDKT. Acute rejection rate and graft survival after ABOi LDKT on a national level have yet to be fully determined. STUDY DESIGN: We studied adult (>18 years) LDKT recipients, from 2000 to 2015, reported to the Scientific Registry of Transplant Recipients. Acute rejection rates in the first post-transplant year (modified Poisson regression) and graft survival (Cox proportional hazards) were assessed by ABO compatibility status (ABOi: 930; ABOc: 89,713). RESULTS: Patients undergoing ABOi LDKT had an AR rate of 19.4% compared with 10.5% for ABOc recipients (p < 0.0001). After adjusting for recipient- and donor-related risk factors, patients undergoing ABOi LDKT were found to have a 1.76-fold greater risk for AR within 1 year of transplantation compared with ABOc LDKT recipients (adjusted relative risk [aRR] 1.76; 95% CI 1.54 to 2.01). Moreover, there was a 2.34-fold greater risk of death-censored graft loss at 1-year post-transplant among ABOi vs ABOc LDKT recipients (adjusted hazard ratio [aHR] 2.34; 95% CI 1.85 to 2.96). CONCLUSIONS: Based on these findings, the low rates of AR and excellent short-term graft survival presented in single center series may not be sustainable on a national level. These findings highlight the potential utility for identification of centers of excellence and regionalization of ABOi LDKT.