OBJECTIVE: Sphingosylphosphorylcholine (SPC) has been reported to activate a variety of G-protein coupled receptors, including S1P(1-5), G2A, GPR4, and OGR1 (GPR68). Interestingly, other structurally related lysophospholipid agonists of these receptors have been shown to exhibit immunomodulatory properties both in vitro and in vivo. These include prevention of tumor necrosis factor-alpha-induced monocyte adhesion to aortic endothelium in mice (sphingosine-1-phosphate via S1P(1-5) receptors) and reduction of organ injury and/or mortality in animal models of sepsis and endotoxemia (lysophosphatidylcholine via G2A). Here, we investigate the effects of SPC on the organ injury/dysfunction caused by systemic administration of lipopolysaccharide and the mechanisms underlying the observed effects of SPC. DESIGN: Prospective, randomized study. SETTING: University-based research laboratory. SUBJECTS: Sixty-one anesthetized male Wistar rats. INTERVENTIONS: Rats received either SPC (10 mg/kg intravenously) or vehicle (phosphate-buffered saline 1 mL/kg intravenously) 15 mins before or 15 mins after induction of endotoxemia with lipopolysaccharide (6 mg/kg intravenously). MEASUREMENTS AND MAIN RESULTS: Treatment with SPC significantly reduced the organ/dysfunction injury caused by lipopolysaccharide. SPC pretreatment significantly reduced the circulating levels of interleukin-1beta and interleukin-6, the expression of CD11b (ligand for intercellular adhesion molecule-1) on circulating polymorphonuclear cells, the expression of proteins of intercellular adhesion molecule-1 (Western blot and immunohistochemistry), cyclooxygenase-2 and nuclear translocation of nuclear factor-kappaB (Western blot analysis), and inducible nitric oxide synthase (immunohistochemistry) as well as the lung injury caused by endotoxemia in the rat. CONCLUSIONS: SPC reduced the organ injury/dysfunction caused by endotoxin in the rat. These beneficial effects of SPC are associated with potent anti-inflammatory effects.