Amiodarone and sotalol are frequently used in the treatment of atrial fibrillation. However, oral and intravenous (IV) therapy with these drugs has suboptimal efficacy and is associated with serious extracardiac side effects. We hypothesized that intrapericardial (IPC) delivery produces antiarrhythmic effects at lower plasma drug concentrations than IV delivery. Goats (n = 27) were randomised into 5 groups receiving either IPC vehicle, amiodarone (IV or IPC) or dl-sotalol (IV or IPC). Epicardial and endocardial atrial effective refractory period and atrial response to burst pacing (rapid atrial response, RAR) were assessed before and after 3 hours of drug infusion at 2 mg.kg.h. IPC delivery produced steeply decreasing drug concentrations from epicardium to endocardium in both atria and ventricles. Plasma drug concentrations were significantly lower in IPC than in IV groups. IPC amiodarone and sotalol reduced epicardial RAR inducibility (-74% +/- 20% and -66% +/- 30%, respectively) compared with IV delivery (-11% +/- 17% and -17% +/- 28%, respectively; P < 0.05). Endocardial RAR inducibility was only reduced in the IPC amiodarone group (-70% +/- 17%, P < 0.05). In conclusion, IPC delivery of amiodarone and sotalol increases atrial drug concentration and antiarrhythmic effects at reduced plasma drug concentrations. These potential benefits are particularly prominent for IPC delivered amiodarone.