BACKGROUND: beta-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 beta-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 beta-blocker therapy for advanced congestive heart failure upwardly regulates the autonomic nervous interaction in synchrony with the evolution of cardiac function performance.