Primary graft dysfunction (PGD) is a major complication following lung transplantation. We reported that anti-type V collagen (col (V)) T cell immunity was strongly associated with PGD. However, the role of preformed anti-col (V) Abs and their potential target in PGD are unknown. Col (V) immune serum, purified IgG or B cells from col (V) immune rats were transferred to WKY rat lung isograft recipients followed by assessments of lung pathology, cytokines, and Pa O 2/Fi O 2, an index of lung dysfunction in PGD. Immune serum, purified IgG, and B cells all induced pathology consistent with PGD within 4 days posttransfer; up-regulated IFN-γ, TNF-α, and IL-1β locally; and induced significant reductions in Pa O 2/Fi O 2. Depleting anti-col (V) Abs before transfer demonstrated that IgG2c was a major subtype mediating injury. Confocal microscopy revealed strong apical col (V) expression on lung epithelial, but not endothelial cells; which was consistent with the ability of col (V) immune serum to induce complement-dependent cytotoxicity only in the epithelial cells. Examination of plasma from patients with or without PGD revealed that higher levels of preformed anti-col (V) Abs were strongly associated with PGD development. This study demonstrates a major role for anti-col (V) humoral immunity in PGD, and identifies the airway epithelium as a target in PGD.