BACKGROUND Interest in combining antiarrhythmic drugs has been prompted by the lack of efficacy of monotherapies and the toxicity resulting from high doses of individual agents. OBJECTIVE We tested the hypothesis that procainamide and sotalol combined have greater beneficial effects on restitution, on the dispersion of refractoriness, and on decreasing the complexity of ventricular fibrillation (VF) than either drug alone. METHODS Six open-chest pigs received intravenous procainamide (15 mg/kg load and 50 microg/kg/min maintenance) followed by sotalol (1.5 mg/kg). Another six pigs received sotalol first and procainamide second. Before drugs and after each drug, 20-second episodes of electrically induced VF were recorded from a 21 x 24 unipolar electrode plaque (2 mm spacing) sutured on the lateral posterior left ventricular epicardium. Restitution properties and dispersion of refractoriness were estimated from activation recovery intervals during pacing. RESULTS The combination of the two drugs reduced the maximum slope of the restitution curve and during VF reduced the number of wavefronts, the activation rate, the percentage of wavefront families exhibiting reentry, and the conduction velocity more than either drug alone. In addition, in the group that received sotalol first, both drugs together reduced the SD and the coefficient of variation of the spatial dispersion of refractoriness compared with baseline. CONCLUSIONS Procainamide and sotalol combined have greater beneficial effects on restitution properties, dispersion of refractoriness, and the complexity of VF than either drug alone compared with baseline.