Prostaglandins (PGs) derived from inducible cyclooxygenase (COX)-2 are important proinflammatory mediators of the host-immune response to infection. Since the role of host-derived PG in human malaria is unknown, plasma bicyclo-PGE2 (a stable catabolite of PGE2), peripheral blood mononuclear cell COX-2 protein, and mRNA were measured in Gabonese children with and without malaria (n=129). Relative to healthy children, bicyclo-PGE2 and COX-2 protein were lower in children with mild (P=.007 and P=.026, respectively) and severe malaria (P=.002 and P=.010, respectively). COX-2 mRNA was also reduced in children with malaria. Investigation of COX-2 regulatory cytokines revealed an inverse correlation (P<.001) between plasma levels of bicyclo-PGE2 and interleukin (IL)-10, a cytokine that suppresses COX-2 expression. On the basis of these results, elevated PGE2 in healthy malaria-exposed children may protect against malaria, whereas IL-10-induced decreases in PGE2 during acute malaria may increase susceptibility to severe disease.