Soluble CD14 (sCD14) mediates lipopolysaccharide (LPS) activation of epithelial cells in vitro and may thereby be harmful in sepsis. sCD14 function was analyzed in sera from 62 patients with septic shock and compared with data from appropriate controls. sCD14 function was measured as sCD14-dependent LPS-induced interleukin (IL)-8 release in the SW620 epithelial cell line. In these cells, IL-8 production correlated with LPS concentration and the amount of sCD14. The effect of natural recombinant sCD14 was maximal at 100 ng/mL and blocked by anti-CD14 antibodies. Patient and control sera (0.5% final concentration) promoted induction of IL-8 by 100 ng/mL LPS in SW620 cells. In sepsis patients (highest serum sCD14), values were significantly higher than in the other groups. The LPS-induced IL-8 response was blocked by anti-CD14 and correlated with the serum CD14 level in sepsis patients. Thus, sCD14 could play a pathogenic role in sepsis.