Unlike agonists such as cytokines or hormones, the biological activity of bacterial lipopolysaccharide (LPS) is substantially modified by serum proteins. One such interaction in serum is with high-density lipoprotein (HDL) forming LPS-HDL complexes. LPS-HDL complexes have been previously shown to have reduced endotoxic activity, for example pyrogenicity, when compared to other forms of LPS in animal models. In this study, we report results of studies comparing the potency of LPS-HDL complexes with uncomplexed LPS as agonists for interleukin-1 (IL-1) production by two different sources of monocytes. LPS-HDL complexes were purified by ultracentrifugation in sodium bromide gradients. The human monocytic cell line THP-1 and the freshly isolated human monocytes, purified by adherence or elutriation from venous blood from healthy donors, were exposed to medium alone containing 1 mg/ml bovine serum albumin, HDL, LPS (parent LPS) and LPS-HDL complexes. mRNA level was analyzed on Northern blot, and cell-associated protein and supernatants were tested for IL-1 production using immunologic and biologic assays. LPS stimulates substantially more IL-1 mRNA and cell-associated IL-1 protein when the monocytes are stimulated with LPS alone versus LPS-HDL. These data suggest that LPS-HDL complexation may contribute to a reduction in endotoxic activities in vivo by preventing LPS (lipid A) from generating important transmembrane signals after binding to cells.