BACKGROUND: Primary graft dysfunction (PGD) remains the leading cause of 30-day mortality post-heart transplantation (HTx). HTx recipients experiencing severe PGD have been found to have high levels of circulating proteins associated with PGD occurrence and post-HTx survival. Whether treating these patients with therapeutic plasma exchange (TPE) can attenuate ongoing immunological and inflammatory processes and improve post-transplant outcomes has not been well-investigated. Therefore, we aim to examine the impact of treatment with TPE on 30-day and 1-year clinical outcomes of patients experiencing severe PGD post-HTx. METHODS: Between 2010 and 2022, we included 42 HTx patients who developed severe PGD. All included patients were placed on veno-arterial extracorporeal membrane oxygenation. We divided these patients into those who received TPE and those who did not (by physician choice). Endpoints included 30-day and 1-year survival, as well as 1-year-freedom from Any-treated rejection (ATR), acute cellular rejection (ACR), antibody-mediated rejection (AMR), biopsy negative rejection (BNR), cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), and freedom from left ventricular dysfunction (LVD) at 1-year post-HTx. RESULTS: Compared to patients who did not receive TPE, those managed with TPE had increased survival rates at 30 days (78.1% vs. 40%, p = 0.007) and at 1-year post-HTx (56.25% vs. 30% p = 0.035). However, no statistically significant differences were recorded in other outcomes of interest, including 1-year freedom from CAV, ATR, ACR, AMR, BNR, NF-MACE, or LVD. CONCLUSION: TPE may serve as a promising therapeutic approach in HTx recipients experiencing severe PGD.