The effects of digoxin on ventricular response during atrial fibrillation (AF) and consequent effects on arrhythmic symptoms have still not been fully explained. This study investigated whether the treatment by digoxin contributes to mid- and long-term stabilization of ventricular cycles in patients with paroxysmal AF. A population of 45 patients with paroxysmal AF underwent 24-hour ECG recordings during each arm of a randomized crossover trial comparing digoxin and placebo. This yielded 30 Holter recordings from 22 patients that contained AF episodes lasting in excess of 2 minutes and with acceptably low Holter noise. Each AF episode was divided into nonoverlapping segments of 30 seconds and the distribution of RR intervals in each segment was compared with the distribution of all other AF segments in the same recording using the Kolmogorov-Smirnov test. The percentage of tests that revealed significant differences at levels of P < or = 0.01, and P < or = 0.001 were sorted according to the time between the segments compared. The comparisons of these results were performed between: (a) all recordings on placebo (n = 16) and all recordings on digoxin (n = 14), and (b) between recordings on placebo and on digoxin in 8 patients in whom paired analysis was possible. Adjacent AF segments (distance 0) differed significantly only in < 30% of both recordings on placebo and on digoxin. However, with increasing the distance between segments, the proportion of the significant differences between RR interval distributions increased more with placebo than with digoxin (P < 10(-300), Chi-square test). Paired data revealed larger differences between placebo and digoxin with increasing distance between segments. Thus in patients with paroxysmal AF, digoxin leads to more reproducible patterns of ventricular cycles that may be better tolerated clinically.