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Macrophages (Mphi) from old mice produce more PGE2 than those from young mice, contributing to the dysregulation of the immune and inflammatory responses with age. This study was conducted to determine the mechanisms of the age-associated increase in Mphi PGE2 production. PGE2 production is influenced by the availability of the substrate arachidonic acid and by activity of the enzyme cyclooxygenase (Cox). We demonstrate that when the substrate is not the limiting factor, Mphi from old mice have significantly higher LPS-stimulated Cox activity than young mice, indicating that the age-associated increase in PGE2 production is due to increased enzyme activity and not to changes in substrate level. Cox activity is determined by the enzyme level and requires hydroperoxide for activation. Of the two Cox isoforms, Cox 1 is constitutively expressed in nearly all cells; whereas Cox 2 is induced by a wide range of ligands. Analysis of accumulated and de novo synthesis of constitutive Cox 1 and inducible Cox 2 proteins showed no age-related difference in Cox 1 protein levels, but Mphi from old mice had higher accumulated and newly synthesized LPS-stimulated Cox 2 protein levels than young mice. Furthermore, Mphi from old mice had higher LPS-stimulated levels of Cox 2 mRNA compared with those from young mice. Clearly, the age-associated increase in LPS-stimulated PGE2 production is due to increased Cox activity resulting from higher Cox 2 protein and mRNA expression. These findings have significant implications for age-associated immune and inflammatory dysregulation as well as the development of preventive and therapeutic strategies against them.