We present two cases of lung-transplanted patients who exhibited: (1) donor-specific anti-HLA antibodies at multiple times after transplantation; (2) continuous, linear, and sub-endothelial C4d deposition concomitantly with detection of anti-HLA antibodies; and (3) biopsy-proven rejections that were refractory to augmented anti-T-cell therapy. In both patients, the pulmonary function progressively diminished, ultimately ending with allograft failure. One patient received a second lung transplant, which allowed us to detect additional donor-specific antibodies directed towards the previous allograft (sponge effect). The presence of donor-specific anti-HLA antibodies in the context of vascular C4d deposition and refractory acute rejection fulfills the criteria for antibody-mediated rejection in these two lung-transplanted patients.