Many of the studies associating digoxin use with increased mortality were conducted before beta-blockers became a standard therapy for heart failure (HF) patients. Our goal was to determine the effect of beta-blockers on the prognosis of patients hospitalized for decompensated HF who receive digoxin therapy at discharge.We analyzed 2402 patients admitted with a primary diagnosis of decompensated HF during the prospective National Heart Failure Survey in Israel. Multivariate modeling was used to determine the effect of beta-blockers and digoxin on 1- and 10-year survival.Patients discharged on digoxin and beta-blockers (DIG+/BB+) had a lower 1-year mortality rate than those discharged on digoxin alone (DIG+/BB−), (31% vs. 44%; p<0.001). Digoxin administration was associated with an increase in adjusted 1-year (Hazard ratio [HR] 1.28; 95% confidence interval (CI) 1.08–1.50) and 10-year mortality risk (HR 1.27; CI 1.16–1.42), whereas beta-blocker administration was associated with a decrease in adjusted 1-year (HR 0.76; CI 0.68–0.87) and 10-year mortality risk (HR 0.83; CI 0.77–0.89; all p<0.001). In comparison to a DIG−/BB+ group serving as a reference, multivariate adjusted HR for DIG+/BB+ and DIG+/BB− groups were 1.36 (CI 1.03–1.91; p<0.001) and 2.01 (CI 1.59–2.85; p<0.001) at 1-year, and 1.04 (CI 0.84–1.28; p>0.1) and 1.37 (CI 1.17–1.76; p<0.001) at 10years.In patients hospitalized with decompensated HF, digoxin administration at discharge is associated with increased 1- and 10-year mortality risk. However, the simultaneous use of beta-blockers and digoxin is associated with lower 1- and 10-year mortality risk when compared to use of digoxin alone.