The pharmacokinetics of the widely used antiarrhythmic agent, procainamide, was studied in rats with extrahepatic biliary obstruction produced by ligation of the common bile duct. Various biological fluids, including plasma, saliva, and urine, were analyzed for procainamide and/or its major metabolite, N-acetylprocainamide. Ligation of the common bile duct immediately prior to intravenous administration of 50 mg/kg procainamide did not alter plasma, saliva, or urine concentrations of procainamide, indicating that biliary excretion was of minor importance in the elimination of procainamide. However, bile duct ligation allowed to persist for 4 days significantly elevated plasma, saliva, and urine levels of procainamide. While the increase in urinary procainamide paralleled the increase observed in plasma, salivary concentrations did not. Bile duct ligation did not appear to impair nonmicrosomal acetylation of procainamide, although a significantly greater amount of unchanged drug was found in the urine after 24 hr. Pharmacokinetic analysis via the two-compartment open model showed that bile duct ligation caused a decrease in overall clearance from approximately 61.94 to 28.71 ml/kg/min. This reduction probably resulted from the decreased microsomal metabolism of procainamide. The significant reduction in the apparent volume of distribution from 3.76 to 2.72 liter/kg could be the result of reduced binding sites. There was also a significant increase in the elimination half-life of procainamide from 47.39 to 78.64 min in bile duct ligated rats.