Methods: We studied 62 clinically stable, nondepressive patients with ischemic HF (New York Heart Association class: I-II), and implantable cardioverter-defibrillator (ICD). Following psychiatric evaluation and quality of life (QoL) assessment, 24-hour electrocardiogram recordings including heart rate variability (HRV) and ICD interrogation were performed every 4 months for 1 year. Ventricular effective refractory period (ERP) at 600-, 500-, and 400-ms cycle length and the inducibility of ventricular tachycardia (VT) were assessed via the ICD. After that, sertraline 50 mg/day was administered for 12 months and the whole evaluation was repeated. Results: Sertraline was associated with fewer ventricular extrasystoles per 24 hours and a significant change in HRV (increase in mean R-R, 5-minute standard deviation of RR intervals, and root mean-square difference of successive RR intervals, and reduction in ultra and very low frequency). It was also followed by an improvement in patients' QoL. A trend toward a decrease was observed in the number of recalled nonsustained VTs. The episodes of sustained VT were not significantly reduced. Ventricular ERPs and VT inducibility remained unaltered. Conclusion: In clinically stable, nondepressive patients with ischemic HF and ICD, sertraline is associated with reduced ventricular extrasystoles, better QoL, and a possible improvement in some HRV indexes. This suggests that SSRIs may have a favorable clinical impact on these patients, independent of the improvement in depressive symptoms. (PACE 2010; 33:1217-1223).