Pregnancy specific glycoproteins (PSG) are secreted into the maternal circulation and may function to regulate the immune system to ensure survival of the fetal allograft. In this study, we have cloned and determined by in situ hybridization the placental sites of expression of Psg18, a murine member of the PSG family that belongs to the Ig superfamily. Recombinant PSG18 and a truncated form containing only the N-terminal domain (PSG18N) were used to treat peritoneal elicited macrophages and RAW 264.7 cells. PSG18 and PSG18N induced IL-10 mRNA expression in the presence and absence of lipopolysaccharide (LPS). IL-10 protein was also detected in the supernatant of macrophages and RAW 264.7 cells following PSG18N treatment, albeit higher concentrations were required in the absence of LPS. In contrast, treatment of these cells with PSG18N resulted in no change in the expression of IL-1β, TNF-α, inducible NO synthase, IL-12p40 and TGF-β mRNA. Taken together, these results suggest that PSG18 selectively up-regulates IL-10 production by macrophages, providing a possible mechanism by which this protein helps promote successful pregnancy.