Introduction: Digoxin is widely used in patients with atrial fibrillation (AF), but its association with adverse outcomes remains controversial. Objective: We aimed to assess the association between digoxin and adverse outcomes in Chinese patients with AF. Methods: We used data from the Chinese Atrial Fibrillation Registry, a prospective, multicenter, hospital-based registry study involving 31 hospitals. In total, 10,472 eligible patients with AF, enrolled from August 2011 to December 2016, were included in this study. The association between digoxin use and all-cause mortality, cardiovascular death, and cardiovascular hospitalization were investigated using Cox proportional hazards models. Results: In total, 1152 (11%) patients were treated with digoxin at baseline. Patients receiving digoxin were older (mean age 69.7 vs. 66.5 years) and had a higher heart rate (92.4 vs. 79.7 beats/min). A higher proportion of patients receiving digoxin therapy had a history of heart failure (62.5 vs. 15.6%), diabetes mellitus (34.4 vs. 24.4%), and persistent AF (67.9 vs. 38.4%). Digoxin use was independently associated with increased all-cause mortality (adjusted hazard ratio (aHR) 1.21; 95% confidence interval (CI) 1.02–1.43; p = 0.031), cardiovascular death (aHR 1.25; 95% CI 1.01–1.55; p = 0.043), and cardiovascular hospitalization (aHR 1.21; 95% CI 1.05–1.39; p = 0.007). The associations were also homogeneous across various subgroups except in patients with and without renal dysfunction (p value for interaction = 0.029). Discussion: In this Chinese AF cohort, for patients who had not undergone ablation, digoxin use was associated with a significant increase in adverse outcomes. Although residual confounders may exist, and serum concentrations of digoxin were unavailable, digoxin should be used with caution in clinical practice, and its effects need to be critically evaluated in randomized trials. Clinical trial registration: URL: http://www.chictr.org.cn/showproj.aspx?proj=5831. Unique identifier: ChiCTR-OCH-13003729. © 2019, Springer Nature Switzerland AG.