The relationship between specific histopathologic findings of chronic rejection (CR) and the clinical course of renal transplant recipients with a chronic progressive decline in allograft function (CPDAF) is unknown. We used one or two hinged regression lines, fitted by least-squares to serial creatinine clearances, to define the onset and clinical course of CPDAF. Biopsies (N = 100) from patients transplanted from 1978 to 1982 were studied retrospectively. Interstitial fibrosis, tubular atrophy, and fibrointimal arterial narrowing were more pronounced in biopsies obtained after, but not before the onset of CPDAF. Interstitial hemorrhage, an infrequent finding in acute vascular rejection, preceded the onset of CPDAF, but the more common histologic findings of acute cellular rejection did not. The severity of histologic features of CR (as reflected by a score combining fibrointimal arterial narrowing, interstitial fibrosis, tubular atrophy, glomerular sclerosis, glomerular mesangial expansion, and glomerular basement membrane reduplication) correlated with the duration of subsequent allograft survival (r = -0.65, P < 0.001). Glomerular size increased after transplantation, but was not different in patients with or without CPDAF, suggesting that mechanisms related to compensatory hypertrophy did not play a major role in the pathogenesis of CR. In summary, the histologic findings of CR did not predict the onset of CPDAF, did not distinguish whether the pathogenesis was mediated by immune or nonimmune events, but did correlate with the duration of subsequent allograft survival.