Previous trials have shown that digoxin was beneficial in patients with heart failure (HF). However, these studies were conducted before the incorporation of beta blockers as standard therapy for patients with HF. The purpose of this study was to determine the effect of digoxin in patients with HF on a contemporary regimen of renin-angiotensin inhibition and beta blockade. In 347 almost exclusively men, data pertaining to the index hospitalization and occurrence of all-cause mortality or readmission for HF were collected. Cox proportional hazard modeling was used. Patients on digoxin therapy had a lower left ventricular (LV) ejection fraction (EF), higher prevalence of previous hospitalizations for HF and atrial fibrillation, and lower prevalence of hypertension. After adjustment for age, LVEF, history of HF hospitalizations, New York Heart Association class, presence of chronic renal insufficiency, presence of atrial fibrillation, and prescriptions for beta blockers and angiotensin converting enzyme inhibitors or angiotensin receptor blockers, HF hospitalizations (hazard ratio 1.08, 95% confidence interval [CI] 0.77 to 1.50, p = 0.66), total mortality (hazard ratio 1.03, 95% CI 0.78 to 1.35, p = 0.85), or the combined end point of HF hospitalization and total mortality (hazard ratio 1.11, 95% CI 0.81 to 1.53, p = 0.52) were not different in patients using digoxin compared with those not using digoxin. Clinical outcomes were not different in subgroups of patients with EF < or =25%, New York Heart Association class III or IV, atrial fibrillation, heart rate < or =60 beats/min, or patients on beta-blocker therapy. In conclusion, digoxin use was not associated with a decrease in HF hospitalizations or overall mortality rates in a cohort of hospitalized patients with HF with LV systolic dysfunction on contemporary background HF treatment including angiotensin-converting enzyme inhibitors and beta blockers.