The role of humoral immunity after lung transplantation remains unclear. In this report, we describe the pathologic findings and clinical course of a case of acute antibody-mediated rejection (AMR) after lung transplantation. After an uncomplicated early course, a 31-year-old man with cystic fibrosis developed acute graft dysfunction 1 month after bilateral lung transplantation. Lung biopsies showed acute pneumonitis with capillary injury, neutrophilic infiltration and nuclear dust. Immunostaining for C4d demonstrated endothelial cell deposition, and circulating donor-specific human leukocyte antigen (HLA) antibodies were identified. Despite severe hypoxemic respiratory failure, he responded well to a regimen consisting of methylprednisolone, plasma exchange, intravenous immunoglobulin and rituximab therapy. He completely recovered clinically although donor-specific HLA antibodies have remained detectable. The incidence of acute AMR after lung transplantation is unknown, but this case fulfills all of the consensus diagnostic criteria, and we suggest that AMR could be an under-recognized cause of acute graft dysfunction.