Central or peripheral administration of the proinflammatory cytokine interleukin (IL)-1beta can impair performance on spatial memory tasks and also elevate circulating concentration of corticosterone. The present experiment provides independent confirmation that intracerebroventricular administration of 10 ng IL-1beta in the rat can have a selective effect on the retrieval of trial unique information about the location of food on an eight-arm radial maze. The probable involvement of corticosterone in IL-1beta-induced memory impairment was indicated by elevated corticosterone levels after IL-1beta administration. Further evidence comes from the blockade of the associated impairment in working memory by coadministration of the glucocorticoid receptor antagonist RU486. Ingestion of diet containing omega-3 fatty acid eicosapentaenoic acid (EPA) is known to antagonize the synthesis of prostaglandin (PG) E2 from aracadonic acid, and the present study confirmed that ethyl EPA (1%) reduced IL-1beta-elevated concentrations of PGE2 and corticosterone. Furthermore, rats given the ethyl-EPA diet for 8 weeks were unaffected by the disruptive effects of IL-1beta on working memory. IL-1beta-induced suppression of mitogen-stimulated release of the anti-inflammatory cytokine IL-10 was also blocked by treatment with ethyl-EPA. Collectively, these data demonstrate that IL-1beta can impair memory function by elevating the concentration of corticosterone and that prior consumption of 1% ethyl-EPA can block both the neuroendocrine and cognitive effects of IL-1beta. These findings in turn may indicate beneficial effects of ethyl-EPA in the treatment of cognitive and affective disorders in which inflammation and stress play a critical role.