When 111In-labeled murine monoclonal antibodies are used in radio-scintigraphic diagnostic procedures, a large fraction of the injected radionuclide is sequestered by the liver. Neither the cells responsible for the uptake nor the mechanism of uptake are known. Little is known about either the site within the liver of antibody metabolism or the form of the products of metabolism. In these studies, the uptake and metabolism of a monoclonal antibody, B6.2 radiolabeled with 111In or 125I [either intact B6.2 or F(ab')2] were determined in rats. One h after injection of either 125I- or 111In-diethylenetriaminepentaacetic acid (111In-DTPA)-labeled B6.2, the predominant liver cell in which the radionuclide was found was the parenchymal cell. At this time, the absolute uptake of 125I in the liver was 0.23 +/- 0.06% (SD) of the injected dose compared to 0.61 +/- 0.06% when the radionuclide was 111In. Removal of the Fc portion of the antibody reduced the absolute liver uptake of 125I to 0.10 +/- 0.01 and the absolute uptake of 111In to 0.16 +/- 0.06. Both radionuclides were still associated predominantly with the parenchymal cell. Using size exclusion high performance liquid chromatography analysis of liver supernatants the metabolism of radiolabeled B6.2 was followed for 24 h. Of the radioactivity recovered, 47.9% of the 125I was precipitable by centrifugation (and presumed bound to cell membranes) while 15.4% was attached to B6.2 found in the cytosol. In contrast, when 111In-DTPA-B6.2 was administered, 16.0% of 111In recovered from the liver was precipitable by centrifugation, and 6.5% was attached to B6.2 found in the cytosol. Sixty % of the 111In was recovered as a low molecular weight (less than 1000) component in the cytosol. This metabolite was not immunoreactive, nor did it comigrate with ferritin, and was resolved into four components by ion exchange high performance liquid chromatography. Of these, only a minor component cochromatographed with an 111In-DTPA standard. These data suggest that the large accretion of radionuclide by the liver is due to uptake of monoclonal antibodies by an Fc receptor-mediated mechanism and the subsequent accumulation of low molecular weight metabolites, presumably 111In-DTPA, attached to one or more amino acids. The reasons for the entrapment of metabolites in the liver are under investigation.