Purpose Despite advances in the field of immunosuppression, obliterative airway disease remains an unsolved problem after clinical lung transplantation and the incidence of chronic renal failure remains high. The efficacy of the highly selective JAK1/3 inhibitor R507 on preclinical airway transplantation was investigated. Methods and Materials Orthotopic Lew-BN trachea transplantations were performed. Treatment groups received oral R507 (60mg/kg BID) or everolimus (4mg/kg QD). Mechanistic studies were performed in vitro using full-thickness human airway epithelium and R507-enriched medium. Results On postoperative day 6, mononuclear CD3 and CD68 graft infiltration were significantly reduced in both treatment groups compared to the control group, but significantly more potently with R507. IFN-γ Elispot frequencies were significantly lower with R507 and everolimus treatment. At 60 days, airway obliteration was significantly reduced from 32±5% in the control group to 24±6% (p=0.004) and 14±5% (p<0.001) in the everolimus and R507 groups, respectively. Using luciferase-positive Lewis donors, we could demonstrate that the obliterated tissue was of donor-origin. The respiratory epithelium was only preserved in the R507 group (88±5%), but widely destroyed in the control and everolimus groups. There was a surge in donor-specific IgG antibody production in the control group that was effectively abrogated with both R507 and everolimus. Side effect screening showed that only everolimus significantly increased creatinine, BUN, cholesterol and triglyceride levels over the study period. In vitro data showed that R507 was not cell toxic. Conclusions R507 is a potent lymphocyte-targeting immunosuppressant without kidney and airway toxicity. It effectively prevents acute graft rejection as well as the development of obliterative airway disease. We believe it will be a valuable drug for lung transplantation.