Allosensitization represents a major barrier to heart transplantation (HTx). We previously reported favorable 1-year outcomes of complement inhibition at transplant in highly sensitized recipients. We now report a longer follow-up. In this single-arm trial (NCT02013037), 20 patients with panel reactive antibodies ≥70% and pre-formed donor-specific antibodies received eculizumab during the first two months post-transplant. The primary endpoint was antibody-mediated rejection (AMR) ≥pAMR2 and/or left ventricular dysfunction. Median follow-up was 4.8 years. Beyond the first year post-transplant, there were no episodes of pAMR2 or greater and no LV dysfunction. There were three deaths, one episode of pAMR1, and one patient with minimal de novo cardiac allograft vasculopathy. Compared to a matched-control group, we observed a non-statistically significant benefit of eculizumab with a lower incidence of primary endpoint or death (primary endpoint: HR=0.50, 95%CI=0.15-1.67, p=0.26; mortality: HR=0.51, 95%CI=0.13-2.07, p=0.35). Our results support the utility of complement inhibition for high-immunological risk recipients. DATA AVAILABILITY STATEMENT: The data that support the findings of this study are available from the corresponding author upon reasonable request.Copyright © 2023. Published by Elsevier Inc.