We present a method for the analysis of antidysrhythmic drugs [procainamide, acecainide (NAPA®), lidocaine, quinidine, disopyramide,N-desisopropyl disopyramide, and propranolol] in serum. The drugs, together with an internal standard, are extracted from 0.2–1.0 ml of serum, separated on an octyl-bonded reversed-phase column using a mobile phase consisting of acetonitrile/phosphate buffer, and monitored by either ultraviolet or fluorescence spectrophotometry. The proposed method offers good reproducibility, sensitivity, linearity, and accuracy. Of more than 50 drugs and metabolites tested for possible interference, only diazepam, flurazepam, and theN-oxide metabolite of quinidine interfere with quinidine analysis, while meperidine coelutes with disopyramide. However, diazepam and flurazepam do not interfere with quinidine analysis with fluorescence detection.