In vitro pretreatment of human monocytes (MO) with low-dose lipopolysaccharide (LPSp) inhibits TNF release in response to subsequent LPSa activation. Septic patients are often indistinguishable from patients with systemic inflammatory response syndrome (SIRS). We hypothesized that in vivo exposure to "septic" stimuli impairs subsequent LPSa-stimulated MO TNF production in vitro. Human peripheral MO were obtained after informed consent from controls or patients with sepsis, SIRS, or posttrauma [ACCP/SCCM definitions]. Cells were plated in vitro, incubated 24 hr, and then stimulated with 0-1000 ng/ml LPSa for 4 hr. Parallel control MO were incubated in vitro with 100 ng/ml LPSp for 24 hr and then stimulated with 1000 ng/ml LPSa for 4 hr. Supernatant TNF (mean U/ml +/- SEM) was measured by bioassay. ANOVA was used to determine statistical significance. In vitro LPSp pretreatment markedly inhibited subsequent LPSa-stimulated TNF release. In vitro LPSa-stimulated TNF release was likewise significantly inhibited with MO from septic patients compared to controls. Inhibition was more profound in septic patients with shock (not shown). No impaired TNF release was seen with MO from SIRS or trauma patients. In conclusion, in vivo preexposure to inflammatory stimuli in septic patients alters monocyte regulation in a manner similar to in vitro endotoxin tolerance. Provocative in vitro monocyte LPS stimulation may distinguish patients with sepsis and SIRS.