SummarySelective Alzheimer disease indicator‐1 (seladin‐1) is a broadly expressed oxidoreductase and is related to Alzheimer disease, cholesterol metabolism and carcinogenesis. The effect of lipopolysaccharide (LPS) on the expression of seladin‐1 was examined using RAW 264.7 macrophage‐like cells and murine peritoneal macrophages. Lipopolysaccharide induced the expression of seladin‐1 protein and messenger RNA in those macrophages. The seladin‐1 expression was also augmented by a series of Toll‐like receptor ligands. The LPS augmented the expression of seladin‐1 via reactive oxygen species generation and p38 activation. Seladin‐1 inhibited LPS‐induced activation of p38 but not nuclear factor‐κB and inhibited the production of tumour necrosis factor‐α in response to LPS. Moreover, seladin‐1 inhibited LPS‐induced osteoclast formation and enhanced LPS‐induced alkaline phosphatase activity. Therefore, it was suggested that seladin‐1 might be an LPS‐responsible gene product and regulate the LPS‐induced inflammatory response negatively.