In order to understand better the role of immune complex metabolism in the pathogenesis of autoimmune diseases, we have investigated the early stages of immune complex uptake by the liver, the major organ responsible for clearance of soluble complexes in the mouse. Livers were perfused in situ via the portal vein over 3 to 5 min with trace amounts of radiolabeled soluble model immune complexes. In 4 nonautoimmune strains (BALB/c, DBA/2, CAF1, NZW) 60 to 72% of the model complexes perfused were taken up and remained in the liver after 20 min of continuous perfusion with oxygenated Krebs-Henseleit buffer. In NZB and NZB/W F1 female mice at ages 0.5 to 11 mo, 66 to 78% of the model complexes remined in the liver. However, when a dose of heat-aggregated human gamma-globulin sufficient to saturate the reticuloendothelial system was perfused 7 min after radiolabeled complexes, 15.2 +/- 7.2% (mean +/- SD) of the complexes were displaced in the nonautoimmune strains. In contrast, 32.6 +/- 10.5% of the complexes were displaced from the liver in NZB and NZB/W F1 female mice (p < 0.001). Thus, although hepatic uptake of immune complexes in autoimmune mice appears to be normal or even enhanced, there may be impaired phagocytosis by the hepatic RES or weaker binding of complexes to the surface of the Kupffer cells. Such surface-bound immune complexes remaining accessible to the circulation may contribute to the autoimmune process.