OBJECTIVE The purpose of this study was to analyze the factors affecting long-term renal function in cyclosporine-treated kidney transplants. METHODS The study population comprised 167 patients with more than 5 years of graft function on cyclosporine therapy. Patients were subdivided into those with a serum creatinine level 2.0 mg/dL or less (group I, n = 123) versus those with a level more than 2.0 mg/dL (group II, n = 44) at 5 years post-transplant. Patient survival, graft survival, rejection episodes, renal function, cyclosporine dose and trough level, and proteinuria were compared in these two groups. RESULTS There was no significant difference between groups I and II in terms of race, sex, donor source, donor age, primary renal disease, retransplants, transfusions, presensitization, histocompatibility locus antigen match, or initial nonfunction. At 6 months post-transplantation, the mean serum creatinine level in group II was significantly higher than group I (P = 0.00001), and this difference increased at subsequent follow-up intervals. The incidence of proteinuria was significantly higher in group II compared with group I (P < 0.001). Renal allograft survival beyond 5 years post-transplant was significantly better in group I compared with group II (P = 0.005). There was no significant difference in the mean cyclosporine dose or the mean cyclosporine trough level between groups I and II at any time following transplantation. The most important difference between groups I and II was the finding of significantly more early (P < 0.001) and late (P < 0.001) rejection episodes in group II. CONCLUSIONS These data suggest that long-term renal function in cyclosporine-treated kidney transplant patients is primarily influenced by the occurrence of early and late rejection episodes rather than by the dosage or duration of cyclosporine therapy.