Heart failure (HF) with preserved systolic function (ejection fraction [EF] >50%) is common, yet no proven therapies exist. Large registries could shed light on what medications may or may not be useful to reduce hospitalization and mortality. The EFFECT Registry, which prospectively enrolled 9,943 patients admitted to the hospital for HF from 1999 to 2001 in 103 hospitals in Ontario, Canada, was used. Patients discharged alive were divided into those with EF >50% and EF <50%. Discharge medications (angiotensin-converting enzyme [ACE] inhibitors, beta blockers [BBs], spironolactone, and digoxin) were examined for their association with HF rehospitalization or death during 1 year. In the HF group with EF >50% (n = 1,026), 199 patients died within 1 year and 349 patients died or were hospitalized for HF within 1 year. In the HF group with EF <50% (n = 1,898), 427 patients died and 720 patients died or were hospitalized for HF. In the HF group with EF >50%, 67% were administered an ACE inhibitor; 32%, a BB; 37%, digoxin; and 12%, spironolactone. No differences were seen in adjusted survival for any medications (ACE inhibitors, BBs, digoxin, or spironolactone) examined in the HF group with EF >50% despite an adjusted survival benefit with ACE inhibitors (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.77 to 0.94), BBs (HR 0.80, 95% CI 0.72 to 0.89), and spironolactone (HR 0.80, 95% CI 0.66 to 0.98) in patients with low EF. In conclusion, none of the medications proved to improve outcomes in patients with HF with low EF showed an association with outcomes in patients with HF and EF >50%, highlighting the need for randomized trial evidence to define therapies that will be beneficial in patients with HF and preserved systolic function.