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Introduction: The diagnosis and treatment of antibody-mediated rejection (AMR) after lung transplantation has recently gained recognition within the transplant community. Extracorporeal photopheresis (ECP), currently used to treat chronic lung allograft dysfunction, modulates various pathways of the immune system known to be involved in AMR. We hypothesize that adding ECP to established AMR treatments could prevent the rebound of donor-specific antibodies (DSA). Objectives: This study aimed to analyze the role of ECP as an add-on therapy to prevent the rebound of DSA. Methods: Lung transplant recipients who received ECP as an add-on therapy for pulmonary AMR between January 2010 and January 2019 were included in this single-center retrospective analysis. Baseline demographics of the patients, as well as their immunological characteristics and long-term transplant outcomes, were analyzed. Results: A total of 41 patients developed clinical AMR during the study period. Sixteen patients received ECP as an add-on therapy after first-line AMR treatment. Among the 16 patients, 2 (13%) had pretransplant DSA, both against human leukocyte antigen (HLA) class I (B38, B13, and C06). Fifteen patients (94%) developed de novo DSA (dnDSA), i.e., 10 (63%) against class I and 14 (88%) against class II. The median time to dnDSA after lung transplantation was 361 days (range 25–2,548). According to the most recent International Society of Heart and Lung Transplantation (ISHLT) consensus report, 2 (13%) patients had definite clinical AMR, 6 (38%) had probable AMR, and 7 (44%) had possible AMR. The median mean fluorescence intensity (MFI) of dnDSA at the time of clinical diagnosis was 4,220 (range 1,319–10,552) for anti-HLA class I and 10,953 (range 1,969–27,501) for anti-HLA class II antibodies. ECP was performed for a median of 14 cycles (range 1–64). MFI values of dnDSA against HLA classes I and II were significantly reduced over the treatment period (for anti-class I: 752; range 70–2,066; for anti-class II: 5,612; range 1,689–21,858). The 1-year survival rate was 55%. No adverse events related to ECP were reported in any of the patients. Conclusions: ECP is associated with a reduction of dnDSA in lung transplant recipients affected by AMR. Prospective studies are warranted to confirm the beneficial effects of ECP in the setting of AMR. [ABSTRACT FROM AUTHOR]