Prostaglandin E (PGE) suppresses macrophage effector mechanisms; however, little is known about the function of PGD in infected alveolar macrophages (AMs). Using serum-opsonized (Ops-) in vitro, we demonstrated that AMs produced PGE and PGD in a time-dependent manner, with PGE levels exceeding those of PGD by 48 h postinfection. Comparison of the effects of both exogenous PGs on AMs revealed that PGD increased phagocytosis and killing through the chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes receptor, whereas PGE had opposite effects, through E prostanoid (EP) receptor 2 (EP2)/EP4-dependent mechanisms. Moreover, PGD inhibited phospholipase C-γ (PLC-γ) phosphorylation, reduced IL-10 production, and increased leukotriene B4 receptor expression. In contrast, exogenous PGE treatment reduced PLC-γ phosphorylation, p38 and nuclear factor κB activation, TNF-α, HO, and leukotriene B, but increased IL-1β production. Using specific compounds to inhibit the synthesis of each PG in vitro and in vivo, we found that endogenous PGD contributed to fungicidal mechanisms and controlled inflammation, whereas endogenous PGE decreased phagocytosis and killing of the fungus and induced inflammation. These findings demonstrate that, although PGD acts as an immunostimulatory mediator to control infection, PGE has immunosuppressive effects, and the balance between these two PGs may limit collateral immune damage at the expense of microbial containment.