Several retrospective studies have raised concerns regarding digoxin therapy in select subgroups of heart failure patients. To assess the impact of digoxin therapy on outcomes in the current era of heart failure therapy, the authors analyzed data representing 5010 patients enrolled in the Valsartan Heart Failure Trial (Val-HeFT) to examine the relationship of baseline digoxin use and all-cause mortality, first morbid event, and heart failure hospitalizations. At baseline, 3374 patients (67%) were receiving digoxin therapy and 1636 (33%) were not. Patients receiving digoxin had features of worse heart failure with higher New York Heart Association class and lower blood pressure, ejection fraction, and β-blocker use (32.1% vs 40.8%). Digoxin use was associated with worse mortality (21.1 vs 15.0%, P<001), first morbid event (34.6 vs 21.7, P<001), and HF hospitalization rate (19.1 vs 10.1%, P<001). After adjustment for baseline group differences including medical therapy and baseline rhythm, patients receiving digoxin remained at a higher risk for all-cause mortality (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.05-1.57), first morbid event (HR, 1.35; 95% CI, 1.15-1.59), and heart failure hospitalization (HR, 1.41; 95% CI, 1.12-1.78). These results remained materially unchanged with propensity matched analysis. No benefit with digoxin use was observed in this study, underscoring the need to reassess the role of digoxin in the contemporary management of heart failure.