We evaluated the effects of long-term digoxin therapy on exercise capacity and on physiological parameters reflecting autonomic tone in 23 patients with mild to moderate heart failure. Before and after maintenance digoxin treatment, all patients underwent cardiopulmonary exercise testing and indexes of heart rate variability (HRV) and baroreceptor sensitivity (BRS) were measured. Long-term digoxin therapy significantly (P < 0.05) increased time domain indexes (rMSSD, pNN50) which reflect parasympathetic activity (from 30 +/- 16 to 37 +/- 14 and from 8 +/- 9 to 12 +/- 7, respectively). High-frequency (HF) and low-frequency (LF) power spectral components also showed a significant increase (from 4.5 +/- 1 to 5.1 +/- 1 and from 5.4 +/- 1 to 5.8 +/- 1, respectively), but the ratio LF/HF decreased, indicating a predominance of vagal activity. The magnitude of these changes exhibited a strong negative Pearson correlation coefficient when compared with initial values before treatment. BRS increased from 2.95 +/- 1.2 to 5.32 +/- 3 ms/mmHg (P < 0.05). Oxygen consumption at peak exercise and at the anerobic threshold increased significantly (from 17 +/- 3 to 19 +/- 3 mL/kg/min and from 14.7 +/- 3 to 16.5 +/- 3 mL/kg/min, respectively). A persistent negative correlation was found between initial values of HRV and the magnitude of changes in exercise capacity. These findings show that long-term digoxin therapy increases vagal activity and improves exercise capacity in patients with mild to moderate heart failure and seems to exert a more marked therapeutic effect on patients with poorer initial autonomic function.