Probucol was given to rats made diabetic by streptozotodn. Compared with diabetic rats not receiving probucol or with nondiabetic rats, probucol lowered the plasma concentrations of trigrycerkies, phospholipids, cholesterol, and apolipoproteln B. The concentrations of serum chylomicrons and very low density lipoprotein (VLDL) were also reduced. In control and diabetic rats, probucol enhanced the clearance of endogenoushy radiolabeled VLDL from the plasma. Clearances from the plasma of rat lymph chylomicrons or chylomicronlike lipkJ emulsions were slow in diabetic rats. Probucol normalized chyiomicron clearance in diabetic rats primarily by restoring hepatic uptake of remnants, which was decreased in diabetes. In diabetic rats, uptake of chyiomicron remnants was increased in a number of extrahepatic tissues, including the heart and kidney. Probucol significantly decreased uptake in some extrahepatic tissues. Increased plasma clearance of VLDL and chylomicrons was associated with an increase in the apolipoprotein CH/Clll and apolipoprotein E/C ratios. Orally administered probucol was specifically incorporated into lymph chylomicrons, and clearance of probucol from the plasma exactly paralleled the clearance of chyiomicron remnants, as traced with radiolabeled cholesteiyl esters. Chylomicron-like emulsions incorporating probucol were exclusively cleared from the plasma by the liver in normal rats. We conclude that in streptozotodn diabetic rats, probucol is an effective hypolipidemic agent because it promotes the clearance of the trigiyceride-rich lipoproteins.