ObjectiveAntiaggregants (Ag) could prevent infective endocarditis (IE) in preclinical studies. In this study we investigated whether Ag or anticoagulants (Ac) were also protective in humans. MethodsIn part I we determined the incidence of IE of bioprosthetic aortic valves (PVE) in 333 consecutive patients who underwent aortic valve replacement for noninfective aortic insufficiency between 2009 and 2019. In part II we retrospectively analyzed data of 137 patients who had developed IE of the native aortic valve (NVE) between 2007 and 2015. Multivariable Fine–Gray and logistic regression models were used to investigate associations between Ag and Ac therapy and IE. ResultsSixteen of 333 (4.8%) aortic valve replacement recipients developed PVE after a median of 3.72 years. There was no association between Ag and PVE, whereas Ac was associated with a higher IE occurrence (no association for vitamin K antagonists but significant for fondaparinux or low molecular-weight heparins; hazard ratio, 4.61; 95% CI, 1.01-21.9). In contrast, among the 137 patients in part II, vitamin K antagonists (odds ratio [OR], 7.52; 95% CI, 2.51-22.6), double antiplatelet therapy (OR, 44.3; 95% CI, 4.83-407), novel oral Ac (OR, 4.17; 95% CI, 1.15-15.1), and fondaparinux or low molecular-weight heparins (OR, 9.87; 95% CI, 1.81-53.9), but not acetylsalicylic acid, were associated with NVE. ConclusionsAc were associated with IE in both cohorts, whereas Ag were not associated with PVE. This might reflect differences in the studied populations, with Ag and Ac being prescribed for conditions associated with long-term IE risk in the NVE cohort. Therefore, determining the potential protective effect of Ag and Ac will necessitate further well–controlled studies.