BACKGROUND: Cardiac resynchronization therapy (CRT) using biventricular pacing improves symptoms and functional capacity in patients with moderate to severe heart failure. The present study examined whether an improvement in ventricular performance from resynchronization therapy changes the autonomic control of heart rate. METHODS AND RESULTS: Heart rate variability (HRV) was examined in 50 patients implanted with the InSync biventricular pacing system who were randomized to therapy-on (n=25) or therapy-off (n=25). HRV was computed as the standard deviation of the atrial cycle length sensed from the system over 2 months of continuous monitoring. HRV was compared between CRT-on and CRT-off groups. HRV was higher in patients randomized to CRT-on compared with CRT-off (148+/-47 ms for CRT-on versus 118+/-45 ms for CRT-off; P=0.02), despite the lack of difference in mean atrial cycle length (844+/-129 ms for CRT-on versus 851+/-110 ms for CRT-off; P=0.82). Changes in plasma catecholamines were not different between the CRT-on and CRT-off groups from baseline to the 3-month follow-up. CONCLUSIONS: Improvement in ventricular performance from CRT shifts cardiac autonomic balance toward a more favorable profile that is less dependent on sympathetic activation.