Background: There are several subtypes of sigma receptor, one of which is found throughout the immune system. SR31747A is a unique sigma ligand that possesses potent immune modulatory properties. Previous in vivo studies have documented that administration of SR31747A in murine models of sepsis resulted in decreased proinflammatory (IL-1, IL-6, TNF-α) and increased anti-inflammatory (IL-10) response (serum, splenocyte). Studies regarding the effect of this sigma ligand on purified macrophages are lacking. We therefore sought to investigate the effect of SR31747A in LPS-stimulated murine macrophages (RAW 264.7). Methods: RAW cells were incubated at 2.5 × 105 cells/well; controls were incubated with media alone, experimental groups contained LPS (0.01 μg) and SR31747A (1 nM, 10 nM, 100 nM, 1 μM, 10 μM). Supernatant and cells were harvested at 24 and 48 h. Concentrations of nitric oxide (Greiss reaction) and IL-10 were determined in the supernatant; cellular IL-10 mRNA was assessed. Results: SR31747A induced a dose-dependent reduction in NO and IL-10 protein release in LPS-stimulated murine macrophages. The decrease in IL-10 protein synthesis was paralleled by a significant dose-dependent reduction in IL-10 mRNA. Conclusion: SR31747A is a novel immunomodulator that down regulates nitric oxide and IL-10 protein and mRNA expression. This in vitro reduction of IL-10 protein and mRNA expression is in contrast to previous in vivo murine studies. These data suggest that peripheral macrophages are not the source of the increased anti-inflammatory (IL-10) response induced by SR31747A.