The pathogenesis of chronic renal allograft rejection is unknown. It is also unclear why cyclosporine has failed to prevent chronic rejection. We examined possible risk factors for graft loss to chronic rejection among 706 renal transplants using the Cox proportional hazards model with fixed and time-dependent covariates. Both the number and the severity of acute rejection episodes were independent risk factors for chronic rejection [relative risk (95% confidence interval) 2.31 (2.04 to 2.60) and 1.53 (1.27 to 1.84), respectively]. Cyclosporine and cyclosporine withdrawal had no effect on chronic rejection. Acute rejections occurring within the first three months after transplantation, when cyclosporine most effectively prevented acute rejection, also had no effect on chronic rejection. Risk factors that were independent of acute rejection and not clearly attributable to immune mechanisms included serum albumin [0.20 (0.10 to 0.38) for each g/dl], proteinuria [1.42 (1.29 to 1.57) for each g/24 hr], and serum triglycerides -1.09 (1.03 to 1.16) for each 100 mg/dl-. These results suggest that the reduction in acute rejection episodes from cyclosporine has failed to reduce graft failure from chronic rejection, possibly because the early (within the first 3 months) and mild acute rejection episodes that are most effectively prevented by cyclosporine do not cause chronic rejection. In addition, the results suggest that there may be a number of nonimmunologic risk factors for chronic rejection.