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Background: The diagnosis of infective endocarditis (IE) can be difficult, particularly if blood cultures fail to yield a pathogen. This study evaluates the potential utility of microbial cell-free DNA (mcfDNA) as a tool to identify the microbial etiology of IE., Methods: Blood samples from patients with suspected IE were serially collected. mcfDNA was extracted from plasma and underwent next-generation sequencing. Reads were aligned against a library containing DNA sequences belonging to >1400 different pathogens. mcfDNA from organisms present above a statistical threshold were reported and quantified in molecules per milliliter (MPM). Additional mcfDNA was collected on each subject every 2-3 days for a total of 7 collections or until discharge., Results: Of 30 enrolled patients with suspected IE, 23 had definite IE, 2 had possible IE, and IE was rejected in 5 patients by modified Duke Criteria. Only the 23 patients with definite IE were included for analysis. Both mcfDNA and blood cultures achieved a sensitivity of 87%. The median duration of positivity from antibiotic treatment initiation was estimated to be approximately 38.1 days for mcfDNA versus 3.7 days for blood culture (proportional odds, 2.952; P = .02771), using a semiparametric survival analysis. mcfDNA (log10) levels significantly declined (-0.3 MPM log10 units, 95% credible interval -0.45 to -0.14) after surgical source control was performed (pre- vs postprocedure, posterior probability >0.99)., Conclusion: mcfDNA accurately identifies the microbial etiology of IE. Sequential mcfDNA levels may ultimately help to individualize therapy by estimating a patient's burden of infection and response to treatment., Competing Interests: Potential conflicts of interests. The authors of this manuscript have conflicts of interest to disclose. V. G. F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, and Roche, and receives royalties from UpToDate. V. G. F. has received grants to his institution from the National Institutes of Health, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Basilea, Janssen. V. G. F. receives support for attending meetings and/or travel to present phase 2 data at 2019 ECCMID from Contrafect. V. G. F. has a sepsis diagnostics patent pending and has stock or stock options at ArcBio and Valanbio and is an Associate Editor at Clinical Infectious Diseases. A. A. A., N. D., E. R. S., and E. C. report they are employees at Karius Inc. D. Hong, D. Hollemon, C. D. V., C. H., L. B., S. D., and J. B. report they are former employees of Karius Inc. A. A. A. and N. D. report registration fees for conferences from Karius, and patents planned, issued or pending from Karius Inc. L. B. reports stock or stock options with Karius, Inc. S. D. reports consulting fees from Karius Inc. C. H. reports stock or stock options from Karius, Inc. D. Hong reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events as an employee of Vir Biotechnology and Janssen Biopharma. E. R. S. reports personal fees from Sema4 and is a former employee of Karius., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)