Purpose: Post-operative vasoplegic syndrome is a dreaded complication in infective endocarditis (IE). Methods and Results: This retrospective study included 166 consecutive patients referred to cardiac surgery for non-shocked IE. Post-operative vasoplegic syndrome was defined as a persistent hypotension (mean blood pressure < 65 mmHg) refractory to fluid loading and cardiac output restoration. Cardiac surgery was performed 7 (5–12) days after the beginning of antibiotic treatment, 4 (1–9) days after negative blood culture and in 72.3% patients with adapted anti-biotherapy. Timing of cardiac surgery was based on ESC guidelines and operating room availability. Most patients required valve replacement (80%) and cardiopulmonary bypass (CPB) duration was 106 (95–184) min. Multivalvular surgery was performed in 43 patients, 32 had tricuspid valve surgery. Post-operative vasoplegic syndrome was reported in 53/166 patients (31.9%, 95% confidence interval of 24.8–39.0%) of the whole population; only 15.1% (n = 8) of vasoplegic patients had a post-operative documented infection (6 positive blood cultures) and no difference was reported between vasoplegic and non-vasoplegic patients for valve culture and the timing of cardiac surgery. Of the 23 (13.8%) in hospital-deaths, 87.0% (n = 20) occurred in the vasoplegic group and the main causes of death were multiorgan failure (n = 17) and neurological complications (n = 3). Variables independently associated with vasoplegic syndrome were CPB duration (1.82 (1.16–2.88) per tertile) and NTproBNP level (2.11 (1.35–3.30) per tertile). Conclusions: Post-operative vasoplegic syndrome is frequent and is the main cause of death after IE cardiac surgery. Our data suggested that the mechanism of vasoplegic syndrome was more related to inflammatory cardiovascular injury rather than the consequence of ongoing bacteremia.