Abstract Background Lung allograft rejection involves the interplay of multiple cellular populations, soluble mediators, and extracellular matrix proteins. The CD44 family of cell surface glycoproteins mediates a variety of cell-cell and cell-matrix interactions including lymphocyte homing to sites of antigenic challenge and fibroblast migration and invasion into extracellular matrix, processes integral to lung allograft rejection. Methods We performed immunohistochemical staining for CD44 on biopsies from allograft recipients with differing rejection experiences: Group 1 ( n = 5 patients/10 biopsies) never exceeded Grade A1 or B2 acute rejection (AR); Group 2 ( n = 7 patients/26 biopsies) had 2 or more episodes of Grade A2 or higher AR and no obliterative bronchiolitis (OB); Group 3 ( n = 6 patients/17 biopsies) had clinical and pathologic OB. Nine infected allograft biopsies, 8 near-normal lung sections (non-transplant controls), and 13 non-transplant biopsies showing bronchiolitis obliterans organizing pneumonia (BOOP), organizing diffuse alveolar damage (DAD), or usual interstitial pneumonia (UIP) were also studied. Results Allograft biopsies demonstrated significantly more CD44 staining among lymphocytes, macrophages, Type II pneumocytes, and respiratory epithelial cells than non-transplant controls, while staining of lymphocytes, macrophages, and Type II pneumocytes did not differ significantly between allograft groups. Fibroblast CD44 staining in Group 3 biopsies significantly exceeded that of controls and Groups 1 and 2, and biopsies with AR and/or OB showed more fibroblast staining than biopsies with BOOP, organizing DAD, or UIP. Alveolar CD44-positive fibroblasts did not predict development of OB, while bronchial CD44-positive fibroblasts were followed in one case by OB. Conclusions These findings suggest that CD44 expression is characteristic of graft-infiltrating inflammatory cells and resident parenchymal cells, and may be related to the initiation and evolution of AR and OB.