To characterize factors of importance for the occurrence of acute rejection as well as study the impact of these episodes on long-term renal survival and function, a total of 819 acute rejection episodes were studied in 951 primary cadaveric donor kidney recipients (CD) and in 396 primary living donor kidney recipients (LD). The patients were treated by three immunosuppressive schedules, namely, CsA given in a high dose, a medium dose, or a low dose. Additionally, all patients received PRED and patients in the low-dose group received AZA. The incidence of acute rejection was higher and occurred earlier after transplantation in the CsA medium dose and low dose groups than in the CsA high dose group (P < 0.05 and P < 0.01, respectively). Although the incidence of first acute rejection was similar in CD and LD patients, 59.1% vs. 60.6%, it was successfully reversed by antirejection treatment in a higher percentage in LD patients. The estimated graft half-life was shorter in patients who had acute rejection episodes than those who did not, 6.6 years vs. 12.5 years in CD patients (P < 0.0001). Renal function at 1-5 years after transplantation was stable, but significantly poorer in CD patients who had experienced acute rejection than in patients who had not, with the mean creatinine clearance rates in the ranges 45-47 vs. 54-60 ml/min in the other groups (P < 0.0001). In a stepwise Cox regression analysis in CD recipients, risk factors for acute rejection were CsA (low dose) treatment schedule, immunization as displayed by presence of panel-reactive antibodies and positive B cell cross-match, young recipient age, disease of diabetes mellitus, and HLA-DR mismatching. In LD recipients, the corresponding risk factors were treatment schedule, young recipient, HLA mismatching, and transplantation from parent to child. Thus, the study has demonstrated some factors of importance for acute rejection episodes in CsA-treated patients as well as showing the detrimental effect of these episodes on long-term graft survival and renal function. These results suggest that a primary aim of future treatment strategies should be to reduce the incidence of these episodes.