Background β-Blocker therapy is believed to modulate the detrimental effect of overcompensating neurohormonal activation in chronic heart failure. However, clinical doubts remain, particularly the physiologic sympathovagal balance. Methods To respond to clinical concern about worsening autonomic nervous perturbation in β-blocker therapy of advanced congestive heart failure, 15 consecutive patients were longitudinally studied to elucidate the evolution of cardiac function versus 24-hour heart rate variability (HRV) before and after 1, 3, and 6 to 9 months of atenolol-combined therapy. Results Two patients died prematurely within 1 month. All 13 surviving patients showed improvement in New York Heart Association functional class, with decrease in left ventricular end-systolic and end-diastolic dimensions and increase in fraction shortening and ejection fraction by echocardiography after at least 3 months of atenolol use. The retarded therapeutic effect was accompanied by a general rise of total, very low, low-, and high-frequency components (9.0 ± 0.5, 8.8 ± 0.5, 6.2 ± 0.6, and 6.1 ± 0.5 vs 10.9 ± 0.3, 10.7 ± 0.4, 8.6 ± 0.3, and 7.8 ± 0.3; all P < .02) of daily HRV. This implied recovery of parasympathetic and baroreceptor function. Return of sympathovagal interaction was further supported by the suppression of Cheyne-Stokes type HRV as detected by Wigner-Ville distribution. Conclusions Long-term β-blocker therapy for advanced congestive heart failure upwardly regulates the autonomic nervous interaction in synchrony with the evolution of cardiac function performance. (Am Heart J 1999;137:658-65.)