Despite significant technological advances, the diagnosis of infective endocarditis (IE) remains a major challenge, and the condition continues to be associated with significant morbidity and mortality. Valvular vegetations have long been the diagnostic and pathologic hallmarks of IE. However, IE can be diagnosed even in the absence of vegetations using the modified Duke criteria. Vegetation-negative endocarditis is rare, and to the present authors' knowledge no cases of septic emboli in the absence of valvular vegetations have been reported. Herein is reported a case of prosthetic aortic valve endocarditis associated with both clinical and radiologic evidence of septic emboli, but in the absence of vegetations on both repeated transesophageal echocardiography and pathologic evaluation. This case highlights the importance of maintaining a high clinical suspicion and a low threshold for the surgical replacement of a possibly infected valve, in patients that meet other clinical criteria for IE, even in the absence of detectable valvular vegetations.