Interleukin (IL)-10 is important for regulating inflammation but whether it protects against infection-related deficits in cognitive function is unknown. Therefore, the current study evaluated sickness behavior, hippocampal-dependent matching-to-place performance and several inflammatory cytokines and neurotrophins in wild-type (IL-10(+/+)) and IL-10-deficient (IL-10(-/-)) mice after i.p. injection of lipopolysaccharide (LPS). Additionally, morphology of dendrites of pyramidal neurons in the dorsal CA1 hippocampus was assessed. Treatment with LPS increased IL-1beta, IL-6, and tumor necrosis factor alpha (TNFalpha) mRNA in all brain areas examined including the hippocampus, in both IL-10(+/+) and IL-10(-/-) mice but the increase was largest in IL-10(-/-) mice. Plasma IL-1beta, IL-6 and TNFalpha were also higher in IL-10(-/-) mice compared to IL-10(+/+) mice after LPS. Consistent with increased inflammatory cytokines in IL-10(-/-) mice after LPS treatment, were a more lengthy sickness behavior syndrome and a more prominent reduction in hippocampal levels of nerve growth factor mRNA; brain-derived neurotrophic factor mRNA was reduced similarly in both genotypes after LPS. In a test of hippocampal-dependent learning and memory that required mice to integrate new information with previously learned information and switch strategies to master a task, IL-10(-/-) mice were found to be less efficient after LPS than were similarly treated wild-type mice. LPS did not affect morphology of dendrites of pyramidal neurons in the dorsal CA1 hippocampus in either genotype. Taken together the results are interpreted to suggest that during peripheral infection IL-10 inhibits sickness behavior and tribulations in hippocampal-dependent working memory via its propensity to mitigate inflammation. We conclude that IL-10 is critical for maintaining normal neuro-immune communication during infection.