The anti-inflammatory cytokine interleukin (IL)-10 is important for regulating inflammation both in the periphery and brain but whether it protects against infection- or age-related psychomotor disturbances and fatigue is unknown. Therefore, the current study evaluated motor coordination, time to fatigue, and several central and peripheral proinflammatory cytokines in male young adult (3 mo) and middle-aged (12 mo) wild type (IL-10^+/+) and IL-10 deficient (IL-10^-/-) mice after i.p. injection of lipopolysaccharide (LPS) or saline. No differences were observed due to age so data from the two ages were pooled and analyzed to determine effects of genotype and treatment. Treatment with LPS increased IL-1, IL-6, and tumor necrosis factor (TNF) mRNA in all brain areas examined in both IL-10^+/+ and IL-10^-/- mice but to a greater extent and for a longer time in IL-10^-/- mice. Plasma IL-1 and IL-6 were increased similarly in IL-10^+/+ and IL-10^-/- mice 4 h after LPS but remained elevated longer in IL-10^-/- mice; whereas TNF was higher in LPS-treated IL-10^-/- mice throughout. LPS treatment did not affect motor performance or motor learning in IL-10^+/+ mice; however, both were reduced in LPS-treated IL-10^-/- mice compared to saline. Furthermore, although LPS reduced the time to fatigue in both IL-10^+/+ and IL-10^-/- mice, the effects were exacerbated in IL-10^-/- mice. Thus, the increased brain and peripheral inflammation induced by LPS in IL-10^-/- mice was associated with increased coordination deficits and fatigue. These data suggest that IL-10 may inhibit motor deficits and fatigue associated with peripheral infections via its anti-inflammatory effects.