The function of renal transplants can deteriorate at any time posttransplant, but the risks and mechanisms may differ at different times posttransplant. Survival of 522 consecutive cadaveric renal transplant recipients followed for at least 6 mo were analyzed, with patient death censored. The overall risk factors in univariate analysis were acute rejection requiring antibody therapy (AR), delayed graft function, elevated serum creatinine at 6 mo, high panel-reactive antibodies, and donor age > or =55 yr, with borderline effects of recipient age and female gender. These risks were studied in each of three intervals posttransplantation: < or =6 mo, 6 mo to 5 yr, and >5 yr. Of the 135 graft failures, 53 occurred < or =6 mo, 61 between 6 mo and 5 yr, and 21 beyond 5 yr. By multivariate analysis. the risks for graft failure in interval < or =6 mo were AR (hazard ratio (HR) = 4.86, P < 0.001); delayed graft function (HR = 1.47, P = 0.06): and high panel-reactive antibodies (HR = 2.04, P = 0.0(3). Between 6 mo and 5 yr, the risks for graft loss were AR (HR = 2.87, P < 0.001) and serum creatinine at 6 mo > or =150 micromol/L (HR = 3.69, P < 0.001). Beyond 5 yr the risk factors were donor age > or =55 yr (HR = 5.87, P = 0.002), with a borderline effect of kidneys from female donors (HR = 2.28, P = 0.07). HLA-A, -B, and -DR matching and presensitization had most of their effect through early AR and impaired function. The results indicate that risks for graft loss are time-dependent: early losses correlate with injury and rejection, but late events correlate with donor age and possibly workload.