Sesame seed oil increases the survival after cecal ligation and puncture in mice and the increased IL-10 levels with non-lethal lipopolysaccharides (LPS) challenge. We showed that sesamin and sesamolin, major lignans of sesame oil, regulated LPS-induced nitric oxide production in the murine microglia and BV-2 cell line. In this study, we studied the effect of sesamin on cytokine production by LPS stimulation. The result showed that sesamin significantly inhibited LPS-stimulated IL-6 mRNA and protein, and to a lesser degree TNF-alpha, in BV-2 microglia. Sesamin and sesamolin also reduced LPS-activated p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB activations. Furthermore, SB203580, a specific inhibitor of p38 MAP kinase, specifically inhibited LPS-induced IL-6 production. These results suggest that sesamin inhibited LPS-induced IL-6 production by suppression of p38 MAPK signal pathway and NF-kappaB activation.