Despite evolving success of mini-invasive techniques in treating cardiac arrhythmias in children, pharmaceuticals remain the cornerstone therapeutic option. Beyond conventional antiarrhythmic agents such as amiodarone, local anesthetics, tranquilizers, anticonvulsants, and neuroleptics exhibit antiarrhythmic properties. H(1)-histamine receptor blockers are widely used in treating allergies in children. Observational studies suggest efficacy of these agents for treating or preventing tachyarrhythmias, although prolongation of QT interval, and ventricular arrhythmias occur. We determined safety and efficacy of antihistamine, quifenadine, versus conventional amiodarone on cardiac rhythm in children with frequent premature beats (PB). One hundred and four patients (mean age 10.8 +/- 3.2 years) with ventricular (n = 65), supraventricular (n = 39) PB were randomized 1:1 to quifenadine (2 mg kg(-1) day(-1); n = 54), or amiodarone (9 mg kg(-1) day(-1), n = 50) arms. Both groups were treated for 2 weeks. All patients underwent 24-hour Holter monitoring 3 times: before at 14-28 days after randomization, and during the follow up at 2-3 months. The mean frequency of PB in quifenadine group was 562 +/- 61 per hour and 597 +/- 78 per hour in the amiodarone-treated children. Full antiarrhythmic efficacy (PB < 75% from baseline) has been achieved in 23/54 (43%) of quifenadine-treated patients, which was less than after amiodarone treatment (37/50, 74%, P = 0.02). Quifenadine was mostly beneficial in children with supraventricular PB and/or bradycardia than in those with ventricular PB; it was associated with a trend toward increased heart rate during day (88.5 +/- 8.4 beats/min) and night (67.3 +/- 6.2) compared with amiodarone (79.6 +/- 7.8 and 56.1 +/- 5.7 beats/min, respectively; P = 0.04). The incidence of side effects in quifenadine group (drowsiness and headache) was low (2%) in contrast to the alarming 40% risk associated with amiodarone therapy. Quifanidine exhibits antiarrhythmic activity in children with frequent PB, without significant QT prolongation, or sinus node depression. Although, H(1)-histamine receptor blocker is less potent than amiodarone, much better safety profile of quifenadine is advantageous, especially in children. Future large trials with proving novel antihistamines pleiotropy are warranted.