Complement-activating anti-HLA donor-specific antibodies (DSAs) are associated with impaired kidney transplant outcome; however, whether these antibodies induce a specific rejection phenotype and influence response to therapy remains undetermined. We prospectively screened 931 kidney recipients for complement-activating DSAs and used histopathology, immunostaining, and allograft gene expression to assess rejection phenotypes. Effector cells were evaluated using human cell cultures. Additionally, we assessed the effect of complement inhibition on kidney allograft rejection phenotype and the clinical response to complement inhibition in 116 independent kidney recipients with DSAs at transplant receiving rejection prophylaxis with eculizumab or standard of care (plasma exchange and intravenous Ig) at ten international centers. The histomolecular rejection phenotype associated with complement-activating DSA was characterized by complement deposition and accumulation of natural killer cells and monocytes/macrophages in capillaries and increased expression of five biologically relevant genes ( , , , , and ) indicative of endothelial activation, IFN response, CD16-mediated natural killer cell activation, and monocyte/macrophage activation. Compared with standard of care, eculizumab specifically abrogated this histomolecular rejection phenotype and associated with a decreased 3-month rejection incidence rate in patients with complement-activating DSAs (56%; 95% confidence interval 95% CI, 38% to 74% versus 19%; 95% CI, 8% to 35%; =0.001) but not in those with noncomplement-activating DSAs (9%; 95% CI, 2% to 25% versus 13%; 95% CI, 2% to 40%; =0.65). In conclusion, circulating complement-activating anti-HLA DSAs are associated with a specific histomolecular kidney allograft rejection phenotype that can be abrogated by complement inhibition.