Heart rate variability is a noninvasive indicator of autonomic nervous system activity. The role of the autonomic nervous system in the genesis of atrial or ventricular arrhythmias is now well established. Little is known about the effects of flecainide on heart rate variability in patients with normal heart structure, the main population receiving flecainide. This study was designed to evaluate the effects of flecainide on heart rate variability in patients without coronary artery disease or congestive heart failure. Time and frequency domain analysis of heart rate variability on 24-hour electrocardiogram recording were assessed in 40 patients with normal echocardiography and without evidence of coronary artery disease before and after 2 months of oral treatment with flecainide (321 +/- 57 mg/day) prescribed for Wolff Parkinson White syndrome with circus movement tachycardia. Flecainide significantly decreased all parameters of heart rate variability in the time domain (median delta% -10% to -25%) and in the frequency domain (median delta% -27% to -38%), including the markers of vagal activity. There was no correlation between plasma concentrations of flecainide and reduction in heart rate variability. It was concluded that in subjects without coronary artery disease or congestive heart failure, flecainide decreases all the measurements of heart rate variability and this decrease is not related to plasma concentrations of flecainide.