Microglia are the major cells involved in neuroinflammation resulting in brain tissue damage during infection and neurodegenerative diseases. In this study, we examined the effects of the monounsaturated fatty acid oleic acid (OA) on LPS-induced proinflammatory mediators production and the mechanisms involved in BV2 microglia. OA inhibited LPS-induced expression of iNOS and COX-2 as well as production of NO and prostaglandin E2. We showed that OA blocked LPS-induced NF-kappaB activation and phosphorylation of inhibitor kappaB kinase (IKK). We also showed that OA inhibited LPS-induced phosphorylation of Akt and p38 MAPK, but not that of ERK. Finally, we showed that OA reduced reactive oxygen species (ROS) accumulation and an anti-oxidant N-acetylcysteine inhibited NF-kappaB transactivation and phosphorylation of IKK and Akt in LPS-stimulated BV2 cells. Taken together, our results suggest that OA shows an anti-inflammatory effect by inhibiting ROS, p38 MAPK, and Akt/IKK/NF-kappaB signaling pathways in LPS-stimulated BV2 microglia.