Antiarrhythmic agents may be beneficial or harmful. Among the harmful effects, or risks, is proarrhythmia. One of several factors that underlie proarrhythmic risk is the presence and nature of any underlying structural heart disease at the time of antiarrhythmic drug administration. The structural disease-antiarrhythmic drug interaction has been best studied and clearly delineated for class I antiarrhythmics. This review provides information to suggest that structural disease can enhance proarrhythmic risk with class III drugs as well, although this is least evident with amiodarone. Particularly pertinent are disorders that prolong action potential duration (such as ventricular hypertrophy or chronic dilatation), inhomogeneous dispersion of refractoriness (including conditions with cellular uncoupling), and reduced ventricular fibrillation threshold. These issues must be considered when choosing an antiarrhythmic drug for atrial and for ventricular arrhythmias and when selecting the dosing and monitoring protocol to be used.