Several compounds of a diastereoisomeric series of 8-substituted 2-methyldecahydroisoquinolines have been found to be equipotent or more potent than quinidine in prolonging the refractory period of isolated guinea pig atria. The effects of selected compounds on the intracellularly recorded transmembrane action potential of isolated canine Purkinje fibers indicated a mechanism of action similar to quinidine in causing a large decrease in the rising velocity of rapid depolarization. Acid dissociation constants and percentage buccal membrane absorption have been determined, in an attempt to correlate these physiochemical properties and the stereochemistry of the derivatives with the observed antiarrhythmic potency. Compounds with high lipophilicity and the trans ring-juncture stereochemistry generally appear to possess superior potency.