Aim: We sought to determine whether there were differences between men and women with acute stroke in their baseline characteristics and outcome in a large cohort of patients randomized in the International Stroke Trial (IST). Methods: Of the 19,435 patients randomized in the IST, 17,370 had an ischemic stroke confirmed by CT scan or autopsy (8,003 female and 9,367 male). In males and females, we compared baseline characteristics (age, frequency of atrial fibrillation, pre-stroke administration of aspirin and systolic blood pressure, conscious level, stroke syndrome) and outcome at 14 days and 6 months (death, complications, dependency, recovery, place of residence). We developed a specific logistic regression model to adjust for case-mix in order to evaluate the separate influence of gender on outcome. Results: Female patients were older, suffered more frequently from atrial fibrillation, had higher systolic blood pressure at randomization and generally had more severe strokes (a higher proportion were unconscious or drowsy or had a total anterior circulation syndrome). Females had higher 14-day and 6-month case fatality and were more likely to be dead or dependent at six months (and consequently more likely to require institutional or residential care). Gender was an independent predictor of death or dependency at 6 months. Conclusions: The adverse effect of female gender on outcome indicates that further research to explore the underlying biological mechanism is justified, and that more intensive acute and long-term treatment may be needed to improve outcome among female patients with stroke.