The purpose of this study was to characterize the histology of antibody-mediated rejection (AMR) in ABO blood-group-incompatible (ABOI) kidney transplants as well as on protocol biopsies performed at the time of stable allograft function. Between 5/99 and 1/02, we performed 32 ABOI kidney transplants (13 A2, 19 non-A2 blood-group living donors). Nineteen biopsies were performed for allograft dysfunction, and 127 protocol biopsies were performed 0, 3, 7, 14, 28 days and 3 and 12 months post transplant. Twenty-five of 32 patients have functioning allografts (mean 585 days post transplant). Nine of 32 (28%) developed clinical AMR. Biopsy revealed glomerular thrombi (78%), mesangiolysis (78%), peritubular capillary C4d staining (56%) and neutrophil infiltration (67%), interstitial hemorrhage and necrosis (56%) and arteriolar thrombi (33%). Subclinical AMR was diagnosed by protocol biopsies in four patients. Findings consisted of glomerular thrombi (100%), mesangiolysis (25%), and C4d staining (100%). In late protocol biopsies performed 214-420 days post transplant, mild mesangiolysis was seen in 2/17 (11.7%), and C4d immunostaining was detected in 3/12 (25%). AMR is characterized by glomerular thrombi, mesangiolysis, peritubular capillary neutrophil infiltration interstitial hemorrhage, necrosis, and C4d deposition. Glomerular thrombi appear early in AMR and may appear prior to graft dysfunction.