It has been suggested that poor long-term prognosis of acute rejection is due to hyperfiltration-mediated injury secondary to the initial renal damage, rather than to ongoing immunological mechanisms. A total of 953 renal transplant recipients was reviewed to examine the effect of acute rejection episodes on graft function and survival; 40% had no rejections, 45% one, 12% two and 3% three. Rejection episodes adversely affected short- and long-term prognosis (5-year survival for no rejections, 62%; one, 34%; two, 26%; three, 19%, P < 0.001) and creatinine clearance at one year (cl 1) (none, 56.7 ml/ min; one, 51.1; two, 52.9; three, 35.2, P < 0.01). This was mainly due to increased graft loss, but patient survival was also reduced (5-year survival for no rejections, 77%; one, 76%; two, 63%; three, 53%, P < 0.05). There was no overall effect of rejection number, independently of cl 1. However, subgroup analysis showed a detrimental effect of rejection number on grafts with high residual function, i. e. cl 1 > 60 ml/min (5-year graft survival none and one, 87%; two and three, 71 %, P < 0.01). Late initial rejection episodes adversely affected prognosis (5-year survival 1-7 days, 34%; 8-60, 31%; 60-300, 21%, P < 0.05) and residual graft function (cl 1 1-7 days, 56.2 ml/min; 8-60, 48.7; 60-300, 44.6, P < 0.01). In conclusion, the poor long-term prognostic effect of rejection episodes is mainly, but not entirely, related to initial graft destruction. Late (> 2 months after transplantation) initial rejection is an important independent risk factor for graft loss.