The ability of fixed macrophages of the reticuloendothelial system to clear circulating immune complexes was studied in 6 patients with primary sclerosing cholangitis, 5 patients with various other forms of chronic liver disease, and 12 normal control subjects. Autologous red cells were radiolabeled with 51Cr and sensitized with anti-Rh(D) immunoglobulin G in vitro. After intravenous infusion of the labeled antibody-coated red cells, the radioactivity content of timed blood specimens was measured. The time required by the reticuloendothelial system to clear one-half the labeled cells from the circulation (t1/2) was then determined. The t1/2 clearance times were significantly prolonged in all 6 patients with primary sclerosing cholangitis, whereas the clearance times in 4 of the 5 liver disease control patients were either normal or shortened. Serum immunoglobulin G and immunoglobulin M immune complex levels did not correlate with t1/2 clearance times. These results suggest that in primary sclerosing cholangitis there is a defect in the ability of fixed macrophages of the reticuloendothelial system to mediate clearance of circulating particles that have been opsonized with immunoglobulin G. This finding further supports recent data that incriminates the immune system in the pathogenesis of primary sclerosing cholangitis.