The anti-inflammatory cytokine interleukin (IL)-10 is important for regulating inflammation in the periphery and brain, but whether it protects against infection- or age-related psychomotor disturbances and fatigue is unknown. Therefore, the present study evaluated motor coordination, time to fatigue, and several central and peripheral proinflammatory cytokines in male young adult (3-mo-old) and middle-aged (12-mo-old) wild-type (IL-10+/+) and IL-10-deficient (IL-10−/−) mice after intraperitoneal injection of lipopolysaccharide (LPS) or saline. No age-related differences were observed; therefore, data from the two ages were pooled and analyzed to determine effects of genotype and treatment. LPS treatment increased IL-1β, IL-6, and TNFα mRNA in all brain areas examined in IL-10+/+and IL-10−/−mice, but to a greater extent and for a longer time in IL-10−/−mice. Plasma IL-1β 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 TNFα was higher in IL-10−/−mice throughout after LPS treatment. Motor performance and motor learning in IL-10+/+mice were not affected by LPS treatment; however, both were reduced in IL-10−/−mice treated with LPS compared with those treated with saline. Furthermore, although LPS reduced the time to fatigue in 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.