Folic acid (3H-pteroylglutamic acid or 75Se-selenofolate) administered free or bound to folate-binding protein (FABP) was rapidly cleared from the plasma but the plasma survival when bound to FABP was longer than unbound during the initial 5 min. 75Se-folate bound to FABP is more rapidly taken up by the liver than when administered as free 73Se-folate. 125I-labeled FABP was rapidly cleared from the plasma (90% in 5 min). The rapid uptake of FABP, a sialoglycoprotein, was inhibited by the preadministration of desialyzed fetuin. Following the hepatic uptake of 75Se-folate/FABP, only free 75Se-folate was found in the bile. The total biliary secretion of 75Se-folate over 240 min was 63% when administered bound to FABP and 33% when administered as free 75Se-folate. The liver retained 33.5% of the 125I activity 5 min following the administration of 125I-FABP, while only 4.46% of the 125I activity was secreted into the bile over 180 min. This data suggests that FABP may play an important role in the enterohepatic circulation of folates by directing nonmethylated folates to the liver.