Objectives: This study sought to explore the gender-related differences in etiology and outcomes in chronic heart failure (HF) patients from 5 randomized trials. Background: Each year, 550,000 new cases of HF are identified; however, there remain limited data on gender-related differences in etiology and outcomes among patients with HF with systolic dysfunction. Methods: We analyzed data from 8,791 men and 2,851 women randomized in 5 clinical trials (PRAISE [Prospective Randomized Amlodipine Survival Evaluation], PRAISE-2, MERIT-HF [Metoprolol Extended Release Randomized Intervention Trial in Heart Failure], VEST [Vesnarinone Trial], and PROMISE [Prospective Randomized Milrinone Survival Evaluation]) to explore gender-related differences in etiology (ischemic vs. nonischemic) and outcomes (all-cause mortality and death or all-cause hospitalization). Hazard ratios (HR), 95% confidence intervals (CIs), and Kaplan-Meier survival curves were generated by gender and etiology. Results: A total of 18% of ischemic and 31% of nonischemic patients were women. Irrespective of etiology, women were older, more ethnically diverse, and had higher systolic blood pressures, more diabetes, and severe HF symptoms, but less often smoked or had prior myocardial infarctions than men. Mean ejection fractions were similar between women (23.6%) and men (23.2%). The 1-year Kaplan-Meier survival estimates varied by gender and etiology (female nonischemics, HR 0.88 [95% CI 0.85 to 0.89]; female ischemics, HR 0.83 [95% CI 0.81 to 0.85]; male nonischemics, HR 0.84 [95% CI 0.83 to 0.85]; male ischemics, HR 0.79 [95% CI 0.78 to 0.81]). After adjustment, female gender (HR 0.77 [95% CI 0.69 to 0.85]) and nonischemic etiology (HR 0.80 [95% CI 0.72 to 0.89]) were associated with longer survival time. Time to death or hospitalization was longer among nonischemics (HR 0.83 [95% CI 0.78 to 0.89], p < 0.0001); however, female gender was not significantly associated with the composite outcome (HR 1.01 [95% CI 0.95 to 1.08]). Conclusions: Our data clarify that outcomes differ by both gender and etiology among patients with HF with systolic dysfunction. Understanding these differences may lead to better management of HF patients and improved overall prognosis.