The histopathology of antibody-mediated rejection in lung allografts, outside of classical hyperacute rejection, has been poorly defined, in part because of the difficulty in identifying potential alloantibodies and in separating alloreactive and nonspecific complement-mediated reactions. In this study, we looked at lung biopsies coinciding with the development of anti-human leukocyte antigen (anti-HLA) antibodies and lung dysfunction in a diverse group of lung transplant recipients over a 3-year period. We identified 23 patients and found that 17 had coexistent high-grade acute cellular rejection, 5 had patchy acute lung injury, and 1 had bronchiolitis at the time that anti-HLA alloantibodies appeared. Capillaritis was seen in 4/22 (18%) cases, usually in the context of cellular rejection. When the 17 cases of acute cellular rejection with coexistent anti-HLA antibodies were compared with a matched group of 26 patients with equivalent cellular rejection grade without anti-HLA antibodies, the only morphologic feature that separated the 2 groups was capillaritis seen in a minority of cases. C4d deposits were seen in both groups, although more frequently in those cases with anti-HLA antibodies (76% vs. 24%). The development of anti-HLA alloantibodies often occurs in the setting of acute cellular rejection, which in only a minority of cases can be identified as likely having an antibody-mediated component. C4d staining does not consistently separate the 2 groups. Identifying and ascribing allograft dysfunction to antibody-mediated rejection related to the development of anti-HLA antibodies is a difficult task that cannot be solved exclusively by morphology and requires significant clinicopathologic correlation.