Abstract Background Chronic aspiration of gastric fluid potentially plays a central role in the pathogenesis of obliterative bronchiolitis, which is often associated with chronic pulmonary allograft failure. It remains unknown whether pharmaceutical-induced increases in gastric pH might effectively prevent any putative pulmonary injury associated with chronic aspiration. Materials and methods To test the hypothesis that neutralization of gastric fluid would affect the development of aspiration-associated obliterative bronchiolitis, an established rat lung transplant model (WKY-to-F344) was utilized. Pulmonary allograft recipients were subjected to eight weekly aspirations of gastric fluid at pH 2.5 (low-pH), gastric fluid at pH 7.4 (neutralized-pH), or saline as a control. Results Histologic analysis revealed that the fraction of airways affected with lesions consistent with obliterative bronchiolitis was 0.55 ± 0.08 (mean ± SEM) in rats receiving aspiration with low-pH gastric fluid, 0.49 ± 0.07 in animals receiving neutralized-pH gastric fluid, and 0.07 ± 0.05 in rats receiving normal saline only. The difference between groups receiving gastric fluid, regardless of pH, was significantly different from the saline control (P < 0.0001), whereas the difference between the groups receiving low-pH gastric fluid and neutralized-pH gastric fluid was not significant (P = 0.75). Conclusions Effective management of gastroesophageal reflux disease in lung transplant recipients should probably include more than neutralization of gastric fluid.