Eicosanoid lipid mediators, including prostaglandin E 2 (PGE 2) and leukotrienes (LTs) B 4 and D 4, are produced in abundance in the infected lung. We have previously demonstrated that individually, PGE 2 suppresses while both classes of LTs augment alveolar macrophage (AM) innate immune functions. In this study, we sought to more appropriately model the milieu at a site of infection by studying the in vitro effects of these lipid mediators on FcγR-mediated phagocytosis when they are present in combination. Consistent with their individual actions, both LTB 4 and LTD 4 opposed the suppressive effect of PGE 2 on phagocytosis, but only LTB 4 did so by mitigating the stimulatory effect of PGE 2 on intracellular cAMP production. Unexpectedly, we observed that IgG-opsonized targets themselves elicited a dose-dependent reduction in intracellular cAMP in AMs, but this was not observed in peritoneal macrophages or elicited peritoneal neutrophils; this effect in AMs was completely abolished by treatment with the LT synthesis inhibitor AA861, the BLT receptor 1 antagonist CP 105,696, and the Gαi inhibitor pertussis toxin. Of two downstream cAMP effectors, protein kinase A and exchange protein activated by cAMP, the ability of PGE 2 to activate the latter but not the former was abrogated by both LTs B 4 and D 4. Taken together, our results indicate that both classes of LTs oppose the immune suppressive actions of PGE 2, with the stimulatory actions of LTB 4 reflecting combinatorial modulation of intracellular cAMP and those of LTD 4 being cAMP independent.