Recent studies have demonstrated that patients with left ventricular assist devices (LVAD) are at increased risk of development of antibody mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) post heart transplantation (HTx). However, the role of pre-existing antibodies (Abs) to HLA in inducing immune responses to cardiac self-antigens (CSAgs) is yet to be defined. In this study, we determined the kinetics of development of Abs to HLA and immune responses to CSAgs during the pre-transplant period in patients on LVAD.Sera from 70 HTx (40 LVAD, 30 Non-LVAD) were enrolled and serially analyzed for Abs to HLA using Luminex and for CSAgs by ELISA. Serum cytokines (IFNγ, IL-17, IL-1β and IL-10) were analyzed by LUMINEX. Sera from 32 age and gender matched normal subjects were the controls.Among LVAD patients, 22/40 (55% vs. 3.1%, p<0.01) had anti-HLA prior to HTx. LVAD with anti-HLA 19/22 (86.4% vs. 13.6%, p<0.01) had Abs to CSAgs. 23/40 (57.5% vs. normal 6.3%, p<0.01) developed MYO-Abs, 25/40 (62.5% vs. normal 3.1%, p<0.01) developed VIM-Abs. In contrast, Non-LVAD group only 1/30 (3.3% vs. 3.1%, p>0.08) had anti-HLA prior to HTx. In this group, 5/30 (16.7% vs. normal 6.3%, p<0.05) developed MYO-Abs, 6/30 (20% vs. normal 3.1%, p<0.05) developed VIM-Abs. No significant difference in Abs to collagen-II (control) were noticed among the three cohorts namely, LVAD vs non-LVAD vs control. Further, patients with Abs to HLA and CSAgs have increased circulating levels of pro-inflammatory cytokines, IFNγ (2.4 fold), IL-17 (1.9 fold), and IL-1β (2.7 fold) along with decrease in IL-10 (3.1 fold).LVAD patients have increased risk for development of anti-HLA prior to transplantation and anti-HLA positive patients further develop immune responses to CSAgs. LVAD patients with anti-HLA and anti-CSAgs have increased circulating pro-inflammatory cytokines prior to transplant which we hypothesize to play a significant role in the development of AMR and CAV following HTx.