The mesenchymal and extracellular matrix alterations that occur in acute and chronic rejection of the lung allograft were studied immunohistochemically, utilizing a wide panel of antibodies. In early rejection, perivascular and peribronchiolar mononuclear infiltrates were associated with basement membrane disruption of the vessels and airways and an ingrowth of muscle-specific actin-, vimentin-positive, desmin-negative spindle cells accompanied by type IV collagenase-positive histiocytes. Subsequent fibrous scarring was manifested by perforation and reduplication of the basement membrane of airways and vessels and dense collagen deposition, primarily type III. As has been suggested in idiopathic pulmonary fibrosis, the fragmentation of basement membranes and the deposition of collagen IV and laminin by mesenchymal cells in vessels and airways may reflect the irreversible fibrosis responsible for allograft dysfunction.