Herein, we reported for the first time that: 1) plasma PLTP activity, but not HDL pool size, was critical for improving the individual survival rate in endotoxemia; 2) the expression of pro-inflammatory cytokines induced by LPS was suppressed by macrophage derived PLTP via the attenuation of NFκB activation; 3) STAT3-SOCS3 pathway was not activated by macrophage derived PLTP; 4) PLTP could bind to LPS and form low cell toxic complex in vitro. This evidence concerns the gene PLTP and serum lipopolysaccharide activity.