Decreased vagal activity and increased sympathetic arousal have been proposed as major contributors to the increased risk of cardiovascular mortality in patients with depression. It was aim of the present study to assess the feasibility of using heart rate variability (HRV) biofeedback to treat moderate to severe depression. This was an open-label study in which 14 patients with different degrees of depression (13 f, 1 m) aged 30 years (18-47; median; range) and 12 healthy volunteers attended 6 sessions of HRV biofeedback over two weeks. Another 12 healthy subjects were observed under an active control condition. At follow up BDI was found significantly decreased (BDI 6; 2-20; median 25%-75% quartile) as compared to baseline conditions (BDI 22;15-29) in patients with depression. In addition, depressed patients had reduced anxiety, decreased heart rate and increased HRV after conduction of biofeedback (p < 0.05). By contrast, no changes were noted in healthy subjects receiving biofeedback nor in normal controls. In conclusion, HRV biofeedback appears to be a useful adjunct for the treatment of depression, associated with increases in HRV.