Heart rate variability (HRV) as determined from 24-h Holter recordings is being recognized as a measure of cardiac autonomic control. In patients surviving myocardial infarction HRV has been established as a useful tool for risk-stratification. The effects of antiarrhythmic agents on HRV, however, have not been extensively studied. The present study therefore examined time- and frequency-domain measures of HRV in 28 patients (10 females, 18 males at a mean age of 59 +/- 15 years) with symptomatic complex ventricular arrhythmias (> 30 VPB/h plus repetitive arrhythmias) before and during treatment with sotalol, a beta-receptor blocking agent with class-III antiarrhythmic activity. Heart rate variability before treatment was independent of the density of spontaneous arrhythmias. Therapy with sotalol resulted in a significant improvement in indices of vagal tone compared to baseline (SDNN 113 +/- 45 vs. 99 +/- 43 ms (p = .05); rMSSD 39 +/- 23 vs. 30 +/- 17 ms (p = .009); pNN50 11.4 +/- 12.5 vs. 6.8 +/- 9.5% (p = .005); HF 13 +/- 7 vs. 11 +/- 7 (p = .048). This improvement was particularly evident in patients with reduced left ventricular function (LVEF < 40%) and was independent of therapy-induced changes in mean heart rate (pNN50 vs. Mean NN r = 0.37; n.s.) or suppression of ventricular arrhythmias (pNN50 vs. In VES/24 h r = 0.41; n.s.). These effects on heart rate variability and thus on cardiac autonomic tone may contribute significantly to the antifibrillatory efficacy profile of sotalol.