To clarify the mechanism of the diarrhea associated with the clinical use of antiarrhythmic drugs we assessed the effects of these agents on transepithelial Na⁺ absorption and Cl^– secretion, on basolateral K⁺ conductance, and on the properties of single basolateral K⁺ channels of rabbit colon epithelium. Quinidine and propafenone, both at 10 M, inhibited Na⁺ absorption by 27 and 38% respectively, compared with 50% with 5 mM Ba²⁺. The other tested class I antiarrhythmics disopyramide, mexiletine, lidocaine, and flecainide decreased Na⁺ current by 9–13%. Procainamide and the class III antiarrhythmics N-acetylprocainamide, sotalol, ibutilide, and amiodarone were no or were very weak inhibitors of Na⁺ absorption. Cl^– secretion, stimulated with the adenosine analogue NECA (5-N-ethylcarboxamide-adenosine), was reduced by 54% with quinidine and by 29% with propafenone compared with 100% with Ba²⁺. Mexiletine, lidocaine, and flecainide inhibited Cl^– secretion by 10–23%, whereas the class III antiarrhythmics were no or were weak inhibitors. Those antiarrhythmics that inhibited Na⁺ and Cl^– transport also reduced basolateral K⁺ conductance, determined in amphotericin B permeabilized epithelia. The activity of the high-conductance, Ca²⁺-activated, voltage-dependent K⁺ (BK_Ca) channel, which is primarily responsible for basolateral K⁺ recycling during Na⁺ absorption, was inhibited by 10–30 M quinidine or propafenone in the form of a rapidly dissociating block. Mexiletine and flecainide inhibited the single channel conductance at higher concentrations; disopyramide, lidocaine, and procainamide were ineffective. In conclusion, the present evidence suggests that the diarrhea caused by class I antiarrhythmic drugs such as quinidine and propafenone is a result of a reduction in basolateral K⁺ conductance and inhibition of BK_Ca channels, thereby impeding transepithelial Na⁺ and water absorption.