Rationale: Obliterative bronchiolitis following lung transplantation is triggered by alloimmunity but ultimately mediated by transforming growth factor-beta 1- dependent airway fibrosis. Objectives: Chronic alcohol use increases transforming growth factor-beta 1 expression and renders the lung susceptible to injury. Therefore, we hypothesized that donor alcohol abuse could prime the lung allograft for obliterative bronchiolitis since many organ donors have a history of alcohol abuse. Methods: Tracheas from control- and alcohol-fed rats (8 wks) were heterotopically transplanted into recipients with varying degrees of alloimmune mismatch and analyzed for obliterative airway disease severity on postoperative day 21. Measurements and Main Results: Although donor alcohol ingestion did not increase the number of antigen presenting cells or infiltrating lymphocytes, it nevertheless increased allograft lumenal collagen content 4-fold compared to allografts from control-fed donors. In parallel, alcohol increased transforming growth factor-beta 1 and alpha-smooth muscle actin expression in allografts. Alcohol amplified airway disease even in isografts with minor alloimmune mismatches. In contrast, it did not cause any airway disease in isografts in a pure isogenic background, suggesting that a minimal alloimmune response is necessary to trigger alcoholinduced airway fibrosis. Conclusions: Although alloimmune inflammation is required to initiate airway disease, alcohol primes the allograft for greater transforming growth factor-beta 1 expression, myofibroblast transdifferentiation, and fibrosis than by alloimmune inflammation alone. This has serious clinical implications, as many lung donors have underlying alcohol abuse that may prime the allograft recipient for subsequent obliterative bronchiolitis.