Background-Although atrial fibrillation (AF) is the most common abnormal heart rhythm and its prevalence continues to rise, there is a marked paucity of effective and safe antiarrhythmic drugs for AF. This study was done to test whether combined use of dofetilide and mexiletine exhibits not only a synergistic effect on AF suppression but also a safer profile in drug-induced ventricular proarrhythmias. \ Methods and Results-The effects of dofetilide plus mexiletine on atrial effective refractory period (ERP), AF inducibility, QT, and QT-related ventricular arrhythmias were studied using the isolated arterially perfused rabbit atrial and ventricular wedge preparations. Dofetilide or mexiletine alone mildly to moderately prolonged atrial ERP, but their combined use produced a markedly rate-dependent increase in atrial ERP. Dofetilide (3 nmol/L) plus mexiletine (10 mu mol/L) increased the ERP by 28.2% from 72.2 +/- 5.7 to 92.8 +/- 5.9 ms (n=9, P< 0.01) at a pacing rate of 0.5 Hz and by 94.5% from 91.7 +/- 5.2 to 178.3 +/- 12.0 ms (n=9, P<0.01) at 3.3 Hz. Dofetilide plus mexiletine strongly suppressed AF inducibility. On the other hand, dofetilide at 10 nmol/L produced marked QT and Tp-e prolongation, steeper QT-BCL and Tp-e-BCL slopes, and induced early afterdepolarizations and torsade de pointes in the ventricular wedges. Mexiletine at 10 mu mol/L reduced dofetilide-induced QT and Tp-e prolongation, QT-BCL and Tp-e-BCL slopes, and abolished early afterdepolarizations and torsade de pointes. Conclusions-In rabbits, combined use of dofetilide and mexiletine not only synergistically increases atrial ERP and effectively suppresses AF inducibility, but also markedly reduces QT liability and torsade de pointes risk posed by dofetilide alone.