Late-life major depression is associated with increased cardiovascular risk and impaired autonomic control of the heart, as evident from reduced heart rate variability (HRV). Moreover, antidepressant drug therapy also might be associated with further reductions of HRV. In the SEEDS study, we investigated whether sertraline associated with physical exercise protocols led to improvements of HRV, compared with antidepressant drug therapy alone. Single-blind randomized controlled trial. Psychiatric consultation-liaison program for primary care. Patients aged 65-85 years with major depression, recruited from primary care. Sertraline plus structured, tailored group physical exercise (S + EX) versus sertraline alone (S) for 24 weeks. HRV indices (RR, percentage of NN intervals greater than 50 msec pNN50, square root of the mean squared differences of successive NN intervals RMSSD, standard deviation of heart rate SDHR, standard deviation of the NN interval SDNN, high-frequency band HF, low-frequency band LF, and their ratio LF/HF) were measured at baseline, week 12, and week 24. Psychiatric and medical assessments. Participants displayed significant improvements of most HRV indices over time, irrespective of the group assignment (pNN50, RMSSD, SDHR, SDNN, HF, LF, and LF/HF). Moreover, patients in the S + EX group displayed greater increases of different HRV indices(RR, pNN50, RMSSD, SDHR, SDNN, HF, and LF) compared with those in the S group. The combination of structured physical exercise and sertraline might exert positive effects on the autonomic control of the heart among older patients with major depression.