The in vivo fate of β-very low density lipoproteins (β-VLDLs) was investigated after Cu2+-mediated oxidative modification (Ox-β-VLDL). Ox-β-VLDL may be physiologically relevant under conditions of defective VLDL removal by the liver (type HI hyperlipoproteinemia) or overloading of the remnant receptor (high cholesterol feeding). On oxidation of β-VLDL, the kinetics of its removal from the blood and uptake by the liver are unchanged. However, in contrast to β-VLDL, which is recognized by the remnant receptor of parenchymal cells, liver uptake of Ox-β-VLDL is mediated mainly by Kupffer cells (65% of liver-associated radioactivity). In vitro competition studies show that the cell association and degradation of iodine-125-labeled Ox-β-VLDL by both liver endothelial and Kupffer cells are only marginally competed for by acetylated LDL (10–20%), while an efficient blockade is noted with Ox-β-VLDL, oxidized low density lipoproteins, or polyinosinic acid (80–90%). The capacity of Kupffer cells to associate with and degradel2SI-Ox-β-VLDL appears to be twofold higher than for endothelial cells. It is concluded that on oxidation of β-VLDL, the recognition system responsible for the uptake of β-VLDL from the blood circulation is shifted from the remnant receptor to a specific oxidized-lipoprotein receptor. The efficiency of the scavenger activity on Kupffer cells will then form the protection system against the prolonged circulation of these atherogenic lipoproteins in the blood.