Propafenone, a sodium channel blocking antiarrhythmic drug with β‐blocking properties, is metabolized to non‐β‐blocking metabolites in part by cytochrome P4502D6. Subtherapeutic doses of quinidine inhibit P4502D6 and increase plasma propafenone in extensive metabolizer subjects, in whom the active enzyme is present. In this study we tested the hypothesis that quinidine would enhance β‐blockade in extensive metabolizers receiving propafenone. Seven extensive and two poor metabolizers received propafenone (225 mg orally every 8 hours) plus quinidine sulfate (60 mg orally every 8 hours) or propafenone plus placebo for 7 days in a randomized, double‐blind, crossover fashion. In extensive metabolizers, the coadministration of quinidine significantly increased the extent of propafenone‐induced β‐blockade, assessed by a decrease in exercise heart rate and by sensitivity to isoproterenol. We conclude that low‐dose quinidine enhances propafenone‐induced β‐blockade in extensive metabolizers. Thus the polymorphic patterns of drug metabolism can result in clinically significant drug interactions on a genetic basis.Clinical Pharmacology and Therapeutics(1994)55,28–