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Early graft failure (EGF) is a major risk factor for death after heart transplantation (Htx). We investigated the predictive risk factors for moderate-to-severe EGF requiring an intra-aortic balloon pump (IABP) or extracorporeal membrane oxygenation (ECMO) circulatory support as treatment after Htx. Between January 2000 and December 2014, 412 consecutive adult patients underwent isolated Htx at our institution. Moderate and severe EGF were defined as the need for IABP and ECMO support, respectively, within 24 h after Htx. All available recipient and donor variables were analyzed to assess the risk of EGF occurrence. Overall, moderate-to-severe EGF occurred in 46 (11.1%) patients. Twenty-nine (63.04%) patients required peripheral or central ECMO support in the treatment of severe EGF and 17 (36.9%) patients required IABP support for the treatment of moderate EGF. The predictive risk factors for moderate-to-severe EGF in recipients, as assessed by logistic regression analysis, were a preoperative transpulmonary gradient > 12 mm Hg (odds ratio [OR] 5.2; P = 0.023), a preoperative inotropic score > 10 (OR 8.5; P = 0.0001), and preoperative ECMO support (OR 4.2; P = 0.012). For donors, the predictive risk factor was a donor score ≥ 17 (OR 8.3; P = 0.006). The absence of EGF was correlated with improved long-term survival: 94% at 1 year and 81% at 5 years without EGF versus 76% and 36% at 1 year (P < 0.001), and 70% and 28% at 5 years (P < 0.001) with EGF requiring IABP and ECMO support, respectively. In-hospital weaned and survived patients after IABP or ECMO treatment for moderate-to-severe EGF had a similar 5-year conditional survival rate as transplant patients who had not suffered EGF: 88% without EGF versus 84% with EGF treated with mechanical circulatory support devices (P = 0.08). The occurrence of EGF is a multifactorial deleterious event that depends on donor and recipient profiles. IABP and ECMO support are reliable treatment strategies, depending on the grade of EGF. Furthermore, surviving patients treated with IABP or ECMO have the same long-term conditional survival rate as patients who have not suffered EGF.