Background Immune responses to mismatched donor HLA antigens play a significant role in the pathogenesis of chronic rejection. The study objective was to evaluate whether erythrocyte bound C4d (E-C4d) is associated with known alloimmune and autoimmune markers of antibody mediated rejection (AMR) following human lung transplantation (LTx). Methods 22 LTx recipients and 15 normal subjects were analyzed for E-C4d using flow cytometry. Development of antibodies (Abs) to donor mismatched HLA (DSA) and Abs to HLA were determined using solid phase method by Luminex. Development of Abs to self-antigens, K-alpha-1-tubulin (KA1T) and collagen V (Col-V) were measured by ELISA. C3d deposition in lung biopsies was determined by immunohistochemical staining. Results Percent E-C4d (%E-C4d) levels in LTx patients were higher compared to normal subjects (19.9% vs. 3.7%, p = 0.02). DSA+ patients had higher E-C4d levels compared to DSA- patients (34.1% vs. 16.7%, p = 0.02). In 5 patients with preformed anti-HLA, E-C4d levels were not significantly different compared to 13 patients with no detectable anti-HLA (p=0.1). Higher E-C4d levels were noted in patients who developed Abs to KA1T (p = 0.02) and Col-V (p = 0.03). Recipients with C3d tissue deposition had higher E-C4d levels compared to patients with C3d negative biopsy results (p = 0.01). Conclusions Increased % E-C4d levels are found in patients with positive DSA, high Abs titers to KA1T and Col-V, and have C3d positive lung biopsy findings. Therefore, % E-C4d can serve as a potential marker for AMR following LTx.