Background.The timing of an acute rejection may have a variable impact on renal allograft survival. To determine whether the time of first acute transplant rejection (ATR) is an independent predictor of long-term allograft survival, we studied 31,600 first cadaveric renal transplants that were functional on the first transplant anniversary, from 217 U.S. centers.Methods.Transplant patients were divided into four groups according to the time to the first ATR: no rejection in year 1 (group I); predischarge ATR (group II); first ATR between discharge and month 6 (group III); and first ATR in months 7-12 (group IV).Results.Four-year allograft survival after year 1, estimated by a Cox proportional hazard model adjusting for 19 cofactors, was 78%, 72%, 69%, and 54% for groups I-IV, respectively (P<0.0001 for each comparison to group I). In those patients who had ATR episodes in more than one time period, later episodes were associated with worse long-term allograft survival, an observation that was independent of previous ATR episodes.Conclusions.We conclude that late occurrence of a first acute rejection portends a worse prognosis for allograft survival after the first year. Later rejections, in combination with previous rejections, also lead to worse long-term allograft survival. Unlike early ATRs occurring in the setting of supervised immunosuppression, late occurring ATR may reflect inadequate immunosuppression from noncompliant behavior or may reflect disruption or lack of immune tolerance to the allograft. Efforts to minimize late transplant loss require a combination of strategies directed at both immunologic and behavioral factors.