Antibody mediated rejection (AMR) remains one of the major challenges for long-term survival following heart transplantation. The immediate and long-term impact of HLA antibodies on graft survival is well established. However, the signaling pathways that are involved in AMR are not well established. Endothelial cell activation by HLA antibodies lead to the activation of several downstream signaling pathways. We utilized an in vitro primary human endothelial cell model treated with humanized monoclonal antibodies to HLA Class I antigens to identify the signaling pathways involved in AMR. A reduction of epidermal growth factor (EGF) levels in endothelial cells was observed following coupling these cells with HLA antibodies. We confirmed this result with ELISA assays of the cell culture supernatant of endothelial cells treated with humanized monoclonal antibodies to HLA class I antigens (mean 32 pg/ml ±SD 4.5 vs control cells 53 ±SD 7.2 pg/ml). Serum EGF levels were evaluated in heart transplant recipients with and without AMR. In patients with AMR (n=16), the mean serum EGF levels were significantly reduced as compared to patients with no AMR (n=22) (151.6± SD 73 pg/mlvs.237.4± SD 52.94 pg/ml, p <0.05). Our data indicates reduced EGF expression in heart transplantation recipients with AMR. This reduction might suggest that EGF could have a protective effect in heart transplant recipients during AMR. This is the first study to demonstrate a correlation between serum EGF levels and AMR in heart transplant recipients.