Obliterative bronchiolitis, characterized histopathologically by airway inflammation and occlusion of small airways by vascularized fibrous tissue, constitutes an important threat to the long-term survival of lung and heart-lung transplant recipients. The pathogenesis of obliterative bronchiolitis is poorly understood, and successful preventative or treatment strategies are not available. We sought to develop a preclinical model system of obliterative bronchiolitis by transplanting murine airway grafts, consisting of tracheas and main bronchi, into the subcutaneous tissue of allogeneically mismatched recipient animals. By 10 days after transplantation, allografts demonstrated subepithelial and/or peritracheal inflammation, epithelial necrosis, and early fibroproliferation. Grafts harvested 21 days after transplantation demonstrated fibroproliferation in the airway wall or lumen in nine of 10 allografts versus 0 of 10 isografts (P = 0.0001). In addition, abnormal epithelium (ie, nonciliated cuboidal, squamous, or absent) was seen in all allografts, while nine of nine isografts demonstrated normal respiratory epithelium (P = 0.0003). Although differences exist between this model and the chronic rejection process in human lung transplant recipients, these findings reproduce the characteristic features of obliterative bronchiolitis and demonstrate that this lesion can result from allograft rejection. This model will be useful for studying the pathogenesis, prevention, and treatment of obliterative bronchiolitis after lung transplantation.