Recent studies have revealed that the immunological function of leukocytes is dependent on their cellular metabolism, and some researchers have advocated the beneficial effects of pioglitazone against sepsis in young mice, although bacterial infections are more prevalent in elderly hosts. Here, we investigated pioglitazone’s preventative effect against sepsis induced by intravenous injection of a lethal dose of Escherichia coli in elderly mice (50–60 wk old) and examined its immunological and metabolic effects on liver leukocytes. Pioglitazone improved bacterial elimination in the peripheral blood, lowered serum pro-inflammatory cytokines (TNF-α, IL-12, IFN-γ), and prevented septic death. It also enhanced bacterial elimination in the liver, by increasing the phagocytic and bactericidal activities of liver F4/80⁺CD11b⁺ recruited macrophages (Mφ), their CD206 expression and reactive oxygen species production. Quantitative PCR revealed that pioglitazone treatment enhanced gene expression of rate-limiting enzymes for glycolysis in hepatic CD11b⁺ cells (including neutrophils and recruited Mφ), and their improved phagocytic and bactericidal activities were abolished by glycolysis inhibiting reagents. These findings present the possibility that pioglitazone strengthens the phagocytic and bactericidal activities of liver recruited Mφ and that these immunological activities are closely associated with their glucose catabolism.