Toxicity of lipopolysaccharide (LPS) (endotoxin) is, to a large extent, mediated by the activation of monocytes/macrophages and subsequent release of monokines, such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). It is known that LPS binds readily to serum lipoproteins and that LPS-lipoprotein complexes are less toxic than unbound LPS. Here we present data analyzing the impact of the LPS-serum interaction at the cellular level. By measuring IL-1 TNF-alpha, and IL-6, the interaction of different LPSs or lipid A with human serum could be shown to prevent the activation of human monocytes. The amounts of LPS inactivated by normal human serum did not exceed 10 ng/ml. The LPS-inactivating capacity of serum was shown to be a function of the lipoproteins. Other serum components, such as naturally occurring anti-LPS immunoglobulin G, complement, or nutritive lipids, had no significant influence in our system. Our experiments suggest that serum lipoproteins control endotoxin-induced monocyte activation and monokine release.