Heart rate variability (HRV) reflects the cardiac autonomic regulation, and reduced HRV is considered a pathophysiological link between depression and cardiovascular mortality. So far, there is only limited information on the effects of venlafaxine and mirtazapine on HRV.We studied 28 nondepressed controls and 41 moderately depressed patients being treated with venlafaxine (n = 20) and mirtazapine (n = 21). Heart rate, blood pressure, and HRV were measured after a 6-day washout as well as after 14 and 28 days of treatment in supine and upright position.We found increased heart rate and reduced HRV in the depressed patients compared with the nondepressed controls. Moreover, HRV total power declined during the treatment period. Medication and remission status after 4 weeks were not related to the change in HRV.We conclude that depression is related to reduced HRV, which might reflect sympathovagal dysbalance. The widely used antidepressants venlafaxine and mirtazapine led to further decline in HRV. Clinicians should consider HRV effects in the selection of antidepressants.