BACKGROUND: C4d deposition in peritubular capillaries (PTCs) is a sign of humoral renal allograft rejection and an independent predictor of graft survival. Few investigators have focused on the meaning of capillary C3 deposition in rejecting grafts. Because C3 production can result from both classic and alternative pathway activation of the complement cascade, it is not clear whether C3 deposition indicates a distinct entity of acute rejection (AR) or merely represents a separate form of C4d-positive AR. METHODS: We examined the deposition of C3d in the PTCs of recipients with AR in the first year posttransplantation (n=30). Clinical outcome variables and histology were compared with C3d-negative control patients (n=82). RESULTS: C3d-positive patients demonstrated more frequent preexisting T-cell antibodies (57%) and more re-transplants (37%), and they received more blood transfusions (mean 10.3 units). C3d-positive patients experienced more frequent multiple AR episodes (57%) and delayed graft function (36.7%). All nine C3d-positive recipients screened for posttransplantation donor-specific human leukocyte antigen antibodies demonstrated positive results. Graft failure occurred in 23% of C3d-positive recipients (7.3% in the control group) (P=0.03). C3d-positive biopsies showed significantly less tubulitis (P=0.03), whereas congestive PTCs with intraluminal accumulation of polymorphonuclear leukocytes were conspicuous. Thrombi, fibrinoid necrosis, and acute tubular necrosis were not more pronounced. In 19% of rejection biopsies, C3d deposition in PTCs was present without C4d deposition. In the remaining biopsies, C3d and C4d deposition was found simultaneously. CONCLUSIONS: The deposition of complement factor C3d in PTCs indicates a variant type of AR characterized by a worse clinical outcome.