AIMS: Atrial fibrillation (AF) patients treated according to a rate-control strategy seem to have excellent outcomes as long as their ventricular response is kept low. However, the stringency of the rate control to adopt with pharmacologic agents is not clearly defined. In particular, the clinical importance of preserving a heart rate (HR) reserve (HRR) during exercise has not yet been investigated. METHODS AND RESULTS: We prospectively analysed the HR response profiles during exercise of 202 patients with permanent AF for whom a strict rate-control strategy was the preferred treatment option. Patients were asked to perform an exercise test on a cycle ergometer until exhaustion. The HRR was defined as the difference between the HR at peak exercise and the resting HR before exercise, divided by the resting HR. Patients were followed-up for at least 24 months or until death or hospitalization for heart failure. The mean resting HR was 80 ± 16 b.p.m. After a median follow-up period of 3 ± 1 years, 31 patients (15.3%) of our initial population (80% male, age 72 ± 12 years) presented either a hospitalization for heart failure (n = 13, 6.4%) or a death (n = 18, 8.9%). Using a univariate analysis, we found that these events correlated with a lower exercise capacity [hazard ratio, HR 0.98, 95% confidence interval, CI (0.96; 0.99), P < 0.001] and a lower HRR [HR 0.30, 95% CI (0.15; 0.60), P < 0.001]. Using a multivariate analysis, both the exercise capacity [HR 0.98, 95% CI (0.97; 0.99), P = 0.008] and the HRR [HR 0.42, 95% CI (0.20-0.87), P = 0.02] remained significantly associated with the outcome. In particular, 4-year survival free from hospitalization for heart failure was better in patients with a preserved HRR (HRR >40%, P < 0.001). No correlation was found between the treatment category (i.e. beta-blockers, calcium channel antagonist, and digoxin) and the HRR. CONCLUSION: An impaired HRR in patients with permanent AF treated according to a strict rate-control strategy is associated with an increased risk of hospitalization for heart failure.