The impact of gender on the presenting characteristics, management, and outcomes in infective endocarditis (IE) has not been adequately studied. The goal of our study was to better understand differences in management and outcome of IE between genders. Data were obtained prospectively from 439 patients in the Duke Endocarditis Database from 1996 to 2004. Baseline characteristics of patients were examined using univariable analysis. Variables associated with gender, in-hospital surgery and long-term mortality in patients with IE were considered for multivariable analysis. Hemodialysis, diabetes mellitus, and immunosuppression were more frequent in female patients with IE. Intracardiac abscesses and new conduction abnormalities were more common in male patients. The following factors were predictive of short-term mortality through univariable analysis: female gender, age, diabetes mellitus, septic pulmonary infarcts, intracranial hemorrhage, infection with Staphylococcus aureus, and persistently positive blood cultures. Female gender was not associated with mortality in an adjusted analysis of short-term outcome. Age, diabetes mellitus, renal failure requiring hemodialysis, cancer, pulmonary edema, systemic embolization, persistently positive blood cultures, and chronic indwelling central catheters but not female gender were associated with long-term mortality using univariable and an adjusted analysis. In both analyses, surgery was associated with improved mortality. Female gender, a history of diabetes mellitus, hemodialysis, and immunosuppression therapy were predictive of a medical management without the use of surgery, although in the adjusted analysis there was no association between surgery and gender. In conclusion, differences between genders in treatment and outcomes frequently reported in patients with IE most likely result from pre- and co-existing conditions such as diabetes mellitus, renal failure requiring hemodialysis, and chronic immunosuppression.