OBJECTIVE This study assessed the safety and efficacy of combined flecainide and amiodarone therapy in controlling refractory tachyarrhythmias in infants. BACKGROUND Single-drug as well as standard combination medical therapy for tachyarrhythmias in infants sometimes fails. In those cases, one may consider interventional therapy. However, this option may carry a high risk of morbidity and mortality in infants. The natural history of tachyarrhythmias in infants often favors eventual resolution and reinforces the importance of selecting an effective medical regimen. METHODS We performed a retrospective analysis of nine infants (median age 2 months) who received combined flecainide and amiodarone therapy for attempted control of refractory tachyarrhythmias. Trough serum drug levels of flecainide were monitored, and 24-h ambulatory electrocardiographic monitoring was used to determine efficacy of therapy. RESULTS Single-drug treatment with flecainide or amiodarone failed in all of the infants studied. An average of four drugs failed (range one to six) before administration of combined flecainide and amiodarone therapy. During combined therapy, the flecainide dose was 70 to 110 mg/m2 per day, and that for amiodarone was 7.5 to 13.5 mg/kg per day for a mean (+/- SD) of 9 +/- 2 days to load and 5 to 12 mg/kg per day as maintenance. Successful control of tachyarrhythmias was demonstrated in seven (78%) of nine infants (95% confidence interval 46% to 99%) (three of three with congenital junctional ectopic tachycardia, three of three with supraventricular tachycardia and one of three with ventricular tachycardia). During combined therapy, flecainide trough levels ranged from 350 to 731 ng/ml. Corrected QT intervals varied from 0.440 to 0.488 ms. No proarrhythmia occurred. None of the infants required a pacemaker, and all had normal left ventricular dimensions and fractional shortening by echocardiography. Eight of nine infants had a structurally normal heart. One infant had surgical correction of an atrioventricular septal defect. CONCLUSIONS Combination therapy with flecainide and amiodarone appears to be safe and effective in controlling refractory tachyarrhythmias in infants. The combination of flecainide and amiodarone may obviate the need for early interventional therapy or may allow delay until the child is older.