Patients with heart failure (HF) and preserved ejection fraction (HF-PEF) constitute up to 30% to 50% of patients with HF, and HF-PEF affects women more often than men. Not much is known about the role of gender in the clinical presentation, symptoms, or disease severity of HF-PEF or about the contribution of these differences to gender differences in morbidity and mortality in patients with HF-PEF. This study examined gender differences in clinical presentation, hospitalization, and mortality in patients with HF-PEF (ejection fraction > or = 50%) enrolled in the ancillary arm of the Digitalis Investigation Group trial. Time-to-event analysis was performed using Cox proportional-hazards modeling. The study cohort included 719 patients (378 men, 341 women). At baseline, compared with men, women were older and had greater clinical severity of HF, as evidenced by worse New York Heart Association functional class, more frequent symptoms and signs of HF, and more treatment with diuretics. Ischemia was identified as the primary cause of HF in 46% of women and 56% of men (p = 0.01). During a median follow-up of 39 months, crude mortality was similar in women and men (24.6% and 24.3%, p = 0.93), but more women were hospitalized for HF (26.7% vs 15.9%, p <0.001). After adjustment for baseline differences, female gender was an independent predictor of lower mortality (hazard ratio 0.59, 95% confidence interval 0.43 to 0.82), but HF hospitalization rates were similar between men and women (hazard ratio 1.09, 95% confidence interval 0.77 to 1.53). In conclusion, although the clinical manifestations of HF appear to be more severe in women with HF-PEF, after adjustment for baseline clinical differences, HF hospitalizations are not increased and survival expectancy is better for women compared with men.