1. The effects of surgical blockage of either or both of the urinary and biliary excretion routes on the elimination of diflunisal (DF) and its conjugates were investigated in pentobarbitone-anaesthetized rats given DF at 10 mg/kg i.v. 2. In control animals the acyl glucuronide and phenolic glucuronide conjugates were excreted predominantly in bile, whereas the sulphate conjugate was eliminated almost exclusively in urine. 3. Bilateral ureter ligation had little effect on DF elimination, except for accumulation of the sulphate conjugate in plasma. Compensatory biliary excretion did not occur. 4. Total plasma clearance of DF decreased from 1.01 to 0.68 ml/min per kg following bile duct ligation. Plasma concentrations and urinary excretion of the glucuronides were elevated. 5. In rats with blockage of both urinary and biliary excretion routes, total plasma clearance of DF decreased to 0.59 ml/min per kg. Both the sulphate and phenolic glucuronide conjugates accumulated in plasma, whereas the acyl glucuronide peaked at 30 min and then declined in parallel with DF. The latter result indicates systemic instability of DF acyl glucuronide with hydrolytic regeneration of DF as the likely major consequence.