Hypothermic oxygenated perfusion (HOPE) is an emerging technique for donor heart preservation that is currently being studied in multiple clinical trials with promising results. When compared to HOPE for other organs, cardiac protocols involve red blood cell (RBC) supplementation, despite absence of comparative evidence for its benefits. In this perspective paper, we discuss the pros and cons of the addition of RBCs during cardiac HOPE. Although the current clinical results with RBC supplementation during HOPE seem promising, potential downsides of RBC supplementation cannot be ruled out. The impact of supplemented RBCs during cardiac HOPE requires further investigation to improve HOPE protocols, to optimize heart preservation using this promising technology.