When gram-negative lipopolysaccharides (LPS) are injected intravenously into experimental animals, approximately one-third of the LPS bind to high-density lipoproteins (HDL) in the plasma and are slowly taken up into tissues by HDL-mediated mechanisms. Molecules of LPS in the plasma that do not bind to HDL are taken up more rapidly by tissues that are rich in phagocytic cells (e.g., liver, spleen). In these experiments we evaluated the effects of several potential host factors on the binding of LPS to HDL and on the tissue uptake of LPS injected intravenously into rats. Antibodies to LPS inhibited LPS binding to HDL and increased the uptake of the injected LPS (as well as the LPS in preformed LPS-HDL complexes) by the liver and spleen. High levels of circulating HDL decreased the uptake of injected LPS and LPS-HDL complexes by the adrenal gland, presumably by occupying tissue receptors for HDL. Pretreating rats with dexamethasone unexpectedly decreased the uptake of injected LPS-HDL complexes by the adrenal gland and increased uptake of LPS by the gland, a result suggesting that this drug has opposing effects on the uptake of HDL-bound and -unbound LPS by the adrenal gland. The host factors studied appear to influence the fate of injected LPS by acting at different sites: IgG antibody to LPS blocks the binding of LPS to HDL in the plasma, whereas all of the factors studied have effects that modulate the uptake of LPS or LPS-HDL complexes or both by the cells of specific tissues.