In patients with atrial fibrillation (AF) and heart failure (HF), beta blockers and digoxin reduce the ventricular rate, but controversy exists concerning how these drugs affect prognosis in this setting. This study compared the effects of beta blocker and digoxin on mortality in patients with both AF and HF. In a single-center institution, patients with AF and HF seen between January 2000 and January 2004 were identified and followed until September 2007. Of 1,269 consecutive patients with both AF and HF, 260 were treated with a beta blocker alone, 189 with beta blocker plus digoxin, 402 with digoxin alone, and 418 without beta blocker or digoxin (control group). During a follow-up of 881+/-859 days, 247 patients died. Compared with the control group, treatment with beta blocker was associated with a decreased mortality (relative risk=0.58, 95% confidence interval 0.40 to 0.85, p=0.005 for beta blocker alone and 0.59, 95% confidence interval 0.40 to 0.87, p=0.008 for beta blocker plus digoxin). By contrast, treatment with digoxin alone was not associated with a better survival (relative risk=0.97, 95% confidence interval 0.73 to 1.30, p=NS). Results remained significant after adjustment for potential confounders and similar when we considered, separately, HF with permanent or nonpermanent AF, presence or absence of coronary disease, and patients with decreased or preserved systolic function. In conclusion, in unselected patients with AF and HF, treatments with beta blocker alone or with beta blocker plus digoxin are associated with a similar decrease in the risk of death. Digoxin alone is associated with a worse survival chance, similar to that of patients without any rate control treatment.