The safety of digoxin therapy in atrial fibrillation (AF) remains ill-defined. We aimed to evaluate the effects of digoxin over beta-blocker therapy in AF. Patients with AF who were treated with either digoxin or a beta blocker from the ESC-EHRA EORP AF (European Society of Cardiology-European Heart Rhythm Association EURObservational Research Programme Atrial Fibrillation) General Long-Term Registry were included. Outcomes of interest were all-cause mortality, cardiovascular (CV) mortality, non-CV mortality, quality of life, and number of patients with unplanned hospitalizations. Of 6377 patients, 549 (8.6%) were treated with digoxin. Over 24 months, there were 550 (8.6%) all-cause mortality events and 1304 (23.6%) patients with unplanned emergency hospitalizations. Compared to beta blocker, digoxin therapy was associated with increased all-cause mortality [hazard ratio (HR) 1.90 (95% confidence interval, CI, 1.48-2.44)], CV mortality [HR 2.18 (95% CI 1.47-3.21)], and non-CV mortality [HR 1.68 (95% CI 1.02-2.75)] with reduced quality of life [health utility score 0.555 (±0.406) vs. 0.705 (±0.346), P < 0.001] but no differences in emergency hospitalizations [HR 1.00 (95% CI 0.56-1.80)] or AF-related hospitalizations [HR 0.95 (95% CI 0.60-1.52)]. On multivariable analysis, there were no differences in any of the outcomes between both groups, after accounting for potential confounders. Similar results were obtained in the subgroups of patients with permanent AF and coexisting heart failure. There were no differences in outcomes between AF patients receiving digoxin with and without chronic kidney disease. Poor outcomes related to the use of digoxin over beta-blocker therapy in terms of excess mortality and reduced quality of life are associated with the presence of other risk factors rather than digoxin per se. The choice of digoxin or beta-blocker therapy had no influence on the incidence of unplanned hospitalizations. © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.