The aim of this study was to assess whether the clinical characteristics, management, and outcomes of infective endocarditis differ in women and men through a prospective observational cohort study at a single tertiary care teaching hospital. From January 2000 to December 2008, 271 new cases of infective endocarditis were diagnosed (183 in men, 88 in women) according to modified Duke criteria, and patients were followed for 1 year. Women were older than men (mean age 63 ± 16 vs 58 ± 18 years, p = 0.006); more women were taking immunosuppressants (14% vs 3%, p = 0.006) and had mitral valve involvement (52% vs 36%, p = 0.02). However, more men had human immunodeficiency virus infection than women. There were no gender differences in Charlson index, regurgitation severity, culprit pathogens, or major complications. When surgery was indicated, women were less likely to undergo the procedure (26% vs 47%, relative risk [RR] 0.4, 95% confidence interval [CI] 0.2 to 0.7), p = 0.001). Mortality tended to be higher in women in the hospital (32% vs 23%, RR 1.58, 95% CI 1 to 2.5, p = 0.05) and at 1 year (38% vs 26%, RR 1.7, 95% CI 1.0 to 2.9, p = 0.04). Surgical treatment was a protective factor against death in the hospital (RR 0.18, 95% CI 0.04 to 0.77, p = 0.02) and at 1 year (RR 0.12, 95% CI 0.03 to 0.48, p = 0.03) after adjustment for age, gender, Charlson index, infection by Staphylococcus aureus, severity at presentation, heart failure, acute renal failure, stroke, and the ejection fraction. In conclusion, women with infective endocarditis were slightly older than men but showed similar co-morbidities. Women underwent surgery less frequently and consequently had worse prognosis than men.