In previous experiments in rats, we have shown that the rapid plasma clearance of a number of clinically important enzymes is due to receptor-mediated endocytosis by Kupffer cells and other resident macrophages. Others have shown that infection of mice with lactate dehydrogenase—elevating virus, a virus that proliferates in macrophages, leads to reduced plasma elimination of these enzymes. This paper integrates these two sets of experiments. Plasma elimination of intravenously injected, radioactively labeled lactate dehydrogenase M4 and mitochondrial malate dehydrogenase in mice was shown to be caused in part by uptake in liver, spleen and bone. Uptake of lactate dehydrogenase M4 by these tissues was, to a large extent, saturable and the two dehydrogenases competitively inhibited each other's clearance. These results suggest that, also in mice, these enzymes are partly cleared from plasma by endocytosis by way of a common receptor on cells (probably macrophages) from liver, spleen and bone marrow. Morphometrical data showed that normal mouse liver contains 23 × 106 Kupffer cells/cm3. This number was reduced to about 30% of that of controls 24 hr after infection of mice with lactate dehydrogenase—elevating virus but returned to normal within the next 9 days. The saturable component of uptake of lactate dehydrogenase M4 by liver, spleen and bone had disappeared 24 hr after infection with the virus, and did not return after the Kupffer cell population had recovered. Our findings suggest that lactate dehydrogenase M4 is, to a large extent, removed from the circulation by way of a receptor on a subpopulation of macrophages that is permissive for replication of lactate dehydrogenase—elevating virus. This subpopulation is destroyed within 24 hr after infection and is replaced during the next 9 days by cells that are not permissive for the virus and lack the receptor. (HEPATOLOGY 1990;12:1192–1199).