This study aimed to investigate the effect of digoxin on mortality and rehospitalization in heart failure with reduced ejection fraction (HFrEF) patients. Heart failure is a clinical syndrome that requires frequent rehospitalization and has a high mortality. This study aimed to investigate the effect of digoxin on mortality and rehospitalization in patients with heart failure with reduced ejection fraction.The study included 326 patients with HFrEF that were hospitalized for decompensation between September 2014 and January 2016. The patients were divided into two groups: digoxin users and a control group. The study's endpoints were cardiovascular death and rehospitalization after 24-month long-term follow-ups.Rehospitalization was lower in patients taking digoxin (25% vs. 47%, p = 0.001). The mean age of patients taking digoxin (n: 78) was 63.7 ± 12.4 years, among which 64% were males. The mean age of the control group was 65.4 ± 11.8 years, among which 74% were males. However, there was no difference in mortality between the two groups (34% vs. 45%, p = 0.10). While Kaplan-Meier curves revealed no significant differences between mortality rates in the groups (log-rank p = 0.508), a statistical difference was found between the groups in rehospitalization rates (log-rank p = 0.013). A multiple linear regression analysis revealed that smoking (HR: 1.97, CI: 1.24-3.11, p = 0.004), systolic blood pressure (HR: 0.983, CI: 0.974-0.992, p < 0.001), atrial fibrillation (HR: 2.09, CI: 1.17-3.72, p = 0.012), C-reactive protein (CRP) (HR: 1.009, CI: 1.003-1.015, p = 0.004), beta-blockers (HR: 0.891, CI: 0.799-0.972, p = 0.009), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (HR: 0.778, CI: 0.641-0.956, p < 0.001), mineralocorticoid receptor antagonists (HR: 0.41, CI:0.26-0.65, p < 0.001), and digoxin use (HR: 0.59, CI: 0.43-0.80, p = 0.001) are independent predictors of rehospitalization in patients with HFrEF.Our results show that digoxin use does not affect mortality in HFrEF patients. However, rehospitalization decreased in patients taking digoxin in HFrEF.