Studies of hepatic and arm uptake, as well as blood clearance of bound and unbound vitamin B12 (I) were performed on 4 individuals free of hepatic or hematologic disease. Unbound I-57 Co was first injected i.v. and changes in hepatic and arm radioactivity were measured. Seven to 10 days following the initial injection of unbound I, pernicious anemia gastric juice (PAGJ) bound I was injected i.v., and similar measurements were carried out for another week. Ten days following injection of unbound I, autologous plasma-bound I was administered i.v., and measurements were performed. PAGJ I increased hepatic uptake, delayed blood clearance, and decreased arm uptake of I when compared with I injected unbound or bound to plasma. The PAGJ I is thus retained longer with greater liver uptake. The results are interpreted as indicating that gastric juice I binders, but not plasma I binders increase hepatic I uptake either by acting at specific receptor sites on the liver cell membrane or by retaining I longer in circulation. This factor depends on a structural feature common to both intrinsic factor related and nonrelated I binders of gastric juice, and is not related to intrinsic factor activity.