The clinical records of 52 patients who were diagnosed clinically as having had infective endocarditis despite negative blood cultures have been reviewed. They differed at presentation from patients with positive blood cultures in more frequent receipt of antibiotics prior to culture and more frequent signs of major systemic emboli and congestive heart failure. Response of culture-negative patients with fever to empiric antibiotic therapy was correlated with survival, in that 92 per cent of the patients who became afebrile within the first week of therapy lived, whereas only 50 per cent of those who did not become afebrile lived. Deaths resulted primarily from major systemic emboli and from uncontrollable congestive heart failure due to valvular insufficiency. In 25 cases, valvular tissue was examined histologically. In 15 cases, vegetations were seen and organisms identified; in six cases, only vegetations were seen; and in four cases (16 per cent), the clinical diagnosis of infective endocarditis was not substantiated in the pathologic report. © 1978.