Antibody-mediated rejection (AMR) is a complication of orthotopic heart transplantation. There is no standard for treatment and it is unclear what role monitoring of donor-directed antibodies (DSA) should play in guiding treatment decisions. In this case series, we describe three patients transplanted at our center who developed AMR and received rituximab as one component of the treatment regimen. We found in these three patients that despite clinical resolution of AMR, high levels of class II donor-directed antibodies persisted. We also summarize our retrospective analysis of 110 heart allografts that had pre- and post-transplant DSA measurements with corresponding EMB and immunofluorescence (IF) during 2005-2011. Our analysis of a subpopulation of 50 informative patients (with DSA measurements, EMB, and corresponding IF) revealed that moderate and severe cardiac allograft vasculopathy were identified more frequently in grafts with DSA than compared to those without DSA.