Objective: Obliterative airway disease, which resembles obliterative bronchiolitis histologically, develops in murine heterotopic tracheal allografts. Chimeric tracheas were used to examine whether donor-type antigen-presenting cells are important in the development of obliterative airway disease. To separate the contributions of CD4+ and CD8+ direct pathways, we transplanted tracheas from knockout mice lacking major histocompatibility complex (MHC) class I or II antigens. Methods: Chimeric tracheas were created via bone marrow transplantation in fully MHC-mismatched combinations. Tracheas from naive B6, autologously reconstituted B6, chimeric B6 bearing recipient-type C3H antigen-presenting cells, MHC class I knockout B6 (B6(I-)), MHC class II knockout B6 (B6(II-)), or C3H mice were transplanted into C3H recipients. The tracheas were harvested at days 14 and 28. Results: At day 28, isografts showed no occlusion, normal respiratory epithelium, and minimal infiltrates. Naive or autologously reconstituted B6, B6(I-) and B6(II-) tracheas showed minimal occlusion at day 14 but contained intraepithelial infiltrates. By day 28, the naive or autologously reconstituted B6 tracheas had occlusion of 69.5% ± 11.6% (mean ± standard error of the mean), and in comparison, B6(I-) and B6(II-) tracheas had occlusions of 53.0% ± 16.3% and 52.2% ± 15.9%, respectively (P = .20, .19). In chimeric B6 tracheas, minimal occlusion was seen at day 14 and remained 33.6% ± 16.2% (P = .039) at day 28. Subtle epithelial changes and minimal infiltrates were seen. Conclusions: Obliterative airway disease appears to involve donor-type antigen-presenting cells and develops in the absence of either MHC class I or II antigens. These findings suggest that either CD8+ or CD4+ direct allorecognition is important in the development of obliterative airway disease.