A total of 1699 patients with living donor transplants and 1795 patients with cadaver donor transplants entered between January 1987 and November 1994 in the North American Pediatric Renal Transplant Cooperative Study registry form the cohort for this report. Failure from chronic rejection occurred in 76 (4.5%) of living donor transplants and 149 (8.3%) of cadaver transplants. Chronic rejection is the leading cause of graft failure, with 27% of living donor and 26.7% of cadaver donor graft failures attributed to chronic rejection. Univariate and multivariate analyses of various risk factors revealed acute rejection (relative risk [RR]=3.1, P<0.001) and greater than two acute rejections (RR=4.3, P<0.001)to be the most common correlates of chronic rejection. Additionally, late initial acute rejection (>365 days; RR=2.3, P<0.001) was also correlated. Cadaver donor source (RR=1.6, P=0.001) and African-American race (RR=1.6, P<0.003) were weaker but significant risk factors. An analysis of cyclosporine dosing revealed tht a dose of <5mg/kg/day at day 30 was also a risk factor (RR=1.5, P=0.027). Our study concludes that acute rejection is the single most critical element in the genesis of chronic rejection. Thus, measures to prevent the first episode of acute rejection could ameliorate the incidence of chronic rejection.