Abstract Background Cardioplegia is an indispensable element in cardiac surgery for left sided infective endocarditis (IE). Crystalloid cardiolegia (CC) as a single or dual-dose is more attractive in complicated IE surgery than repeated, every 15-20 min, administration of blood cardioplegia (BC). Recently, blood cardioplegia was shown to reduce the systemic inflammatory response to cardiopulmonary (CPB) compared to crystalloid cardioplegia. As the systemic inflammatory response after surgery for IE endocarditis is more exaggerated than in non-IE valve surgery, it is important to investigate impact of the two solutions on outcome after IE surgery. Methods We retrospectively analyzed data of all patients (n=581) with endocarditis who underwent cardiac valve surgery at our institution between January 2007 and March 2018. The primary endpoint was 30-day mortality, secondary endpointwas the length of intensive care unit (ICU) stay. Nearest neighbor propensity matching with a caliper of 0.01 was performed to adjust for differences in basal characteristics between patients who received Calafiore BC vs Bretschneider CC. Results Patients who received CC were older (67 vs 63, p<0.01) had greater incidence of large vegetations (42.7% vs 32.3%, p<0.01), prosthetic valve endocarditis (30.8% vs 17.3%, p<0.01) and mitral valve endocarditis (54.6 vs 43.6 p<0.01). Logistic regression in the raw data revealed a higher mortality rate and longer LOS in ICU for the patients who received CC. After matching, CC was still associated with higher 30-day mortality (24.4% vs 15.9%, p=0.01) and longer ICU-stay (median: 6, IQR: 9 vs median: 3, IQR: 6, p<0.01). Conclusions Administration of blood cardioplegia during cardiac surgery for infective endocarditis may be associated with lower 30-day mortality and shorter ICU-stay compared to using crystalloid solution.