BACKGROUND: Donor-specific antibodies (DSAs) after lung transplantation correlate with poor outcomes. The ideal treatment strategy for antibody-mediated rejection AMR is not defined. Our institution implemented an aggressive multimodality protocol for the treatment of suspected AMR. METHODS: Lung transplant recipients with suspected AMR were treated with a standardized protocol of plasma exchange, steroids, bortezomib, rituximab, and intravenous immune globulin. Primary outcome was DSA clearance at 6 months in those alive. Secondary endpoints included preserved allograft function at 6 months, survival at 6 and 12 months and complications due to the protocol. RESULTS: Sixteen lung transplant recipients with documented DSA and allograft dysfunction were included in the analysis. Of the 16 patients, 11 survived to 6 months. Three of those 11 patients (27%) cleared all DSAs within 6 months of the protocol. Four of the 11 patients (36%) had preserved allograft function at 6 months. Overall 12-month patient survival was 56%. Complications included thrombocytopenia (50%) and abdominal pain or gastrointestinal discomfort (18.7%). CONCLUSIONS: This multimodality protocol resulted in clearance of DSAs and preserved lung function in a minority of lung transplant recipients with suspected AMR surviving to 6 months after therapy. There were significant side effects of the protocol.