BACKGROUND: Few data exist on the long-term changes and the prognostic value of heart rate variability (HRV) assessed by implanted devices in heart failure (HF) patients treated with resynchronization therapy (CRT). AIMS: To analyze the long-term changes in the standard deviation of 5-minute median atrial-atrial sensed intervals (SDANN), and assess its role in predicting CRT efficacy and major cardiovascular events. METHODS AND RESULTS: We included 509 consecutive patients implanted with CRT devices. At 12-month follow-up, 44 patients had died and 86 patients had at least one HF hospitalisation. A significant increase in SDANN occurred after 4 weeks of CRT (from 69+/-22 ms to 82+/-27 ms, p<0.001). A further increase in SDANN was observed 6 months after implantation. Multivariable analysis identified SDANN as the sole predictor of major cardiovascular events (p=0.03) among several baseline parameters. SDANN< or =65 ms at the first week and SDANN< or =76 ms after 4 weeks of CRT yielded the best prediction of all-cause mortality and urgent heart transplantation on Kaplan-Meier analysis (log-rank test p=0.015 and p=0.011, respectively for week 1 and 4 values). Moreover, relative reduction in LVESV after CRT significantly correlated with SDANN at week 1 (r=-0.596, p=0.012), and week 4 (r=-0.703, p=0.001). CONCLUSIONS: Device-monitored HRV is a useful tool to identify, early after implantation, patients with a low likelihood of long-term benefits from CRT and at high risk for cardiovascular events.