Exaggerated proinflammatory cytokine responses can be observed with aging, and reduced levels of the anti-inflammatory cytokine IL-10 may contribute to these responses. IL-10 can reduce IL-6, IL-1β, and TNF-α expression in nonmuscle tissues; however, no studies have examined the combined effects of IL-10 and age on cytokine responses in skeletal and cardiac muscle. These experiments tested the hypothesis that the absence of IL-10, in vivo, is associated with greater IL-6, TNF-α, and IL-1β responses to an inflammatory challenge in skeletal and cardiac muscle and that aging exaggerates these responses. We compared IL-6, IL-1β, and TNF-α mRNA and protein levels in skeletal and cardiac muscle of young (4 mo) and mature (10–11 mo) wild-type (IL-10^+/+) and IL-10 deficient (IL-10^−/−) mice following LPS. Skeletal and cardiac IL-6 mRNA and protein were elevated by LPS for IL-10^+/+ and IL-10^−/− mice with greater responses in the IL-10^−/− mice (P < 0.01). In skeletal muscle these effects were greater in mature than young mice (P < 0.01). IL-1β mRNA and protein responses to LPS were greater in cardiac muscle of young but not mature IL-10^−/− mice compared with IL-10^+/+ (P < 0.01). However, IL-1β responses were greater in mature than young mice, but only in IL-10^+/+ groups (P < 0.05). The absence of IL-10 was associated with higher TNF-α protein levels in cardiac muscle (P < 0.05). The results provide the first in vivo evidence that the absence of IL-10 is associated with a greater IL-6 response to LPS in skeletal and cardiac muscles, and in skeletal muscle aging further exaggerates these responses.