We prospectively monitored clinical data and renal function at minimum monthly intervals in 220 patients who received kidney transplants at our institution between January 1, 1976 and December 31, 1982. All had functioning allografts for a year or longer. During a mean follow-up of 54.7 (14-96) months, 61 patients (28%) developed 74 late rejections, of which 23 (31%) were symptomatic and 51 (69%) were asymptomatic. Twenty-one rejections in 15 patients were diagnosed on clinical grounds (group A) and 53 rejections in 46 patients were diagnosed by renal histology (group B). Of this latter group, 26 biopsy specimens showed histological evidence of acute cellular rejection (ACR), 17 showed acute cellular rejection and chronic rejection (ACR + CR), and 10 showed chronic rejection (CR) only. Of the 26 ACRs, 10 (39%) responded fully to antirejection therapy, 14 (54%) responded partially, and 2 (7%) did not respond. Of the 17 ACR + CRs, the response to therapy was complete in 5 (29%), partial in 8 (47%), and none in 4 (24%). Of the 10 CRs, therapeutic response was none in 7 (70%) and partial in 3 (30%). During the period of our observation, 96% of patients with ACR had preservation of graft function (14% dead, 82% alive) and 4% had returned to dialysis. Among the patients with ACR + CR, 87% had preserved graft function (13% dead, 74% alive) and 13% returned to dialysis. Of the patients with CR, only 33% had preserved renal function (11% dead, 22% alive) and 67% returned to dialysis. Our observations indicate that (1) routine monitoring of renal function at minimum monthly intervals is essential to diagnose and treat these late rejections, which are often asymptomatic; (2) renal histology provides valuable diagnostic and prognostic information in the management of patients with late allograft rejection.