Cyclooxygenase (COX) -1 and -2 metabolize arachidonic acid to prostanoids and reactive oxygen species, major players in the neuroinflammatory process. While most reports have focused on the inducible isoform, COX-2, the contribution of COX-1 to the inflammatory response is unclear. In the present study, the contribution of COX-1 in the neuroinflammatory response to intracerebroventricular lipopolysaccharide (LPS) was investigated using COX-1 deficient (COX-1^-/-) mice or wild-type (COX-1^+/+) mice pretreated with SC-560, a selective COX-1 inhibitor. Twenty-four hours after lipopolysaccharide (LPS) injection, COX-1^-/- mice showed decreased protein oxidation and LPS-induced neuronal damage in the hippocampus compared with COX-1^+/+ mice. COX-1^-/- mice showed a significant reduction of microglial activation, proinflammatory mediators, and expression of COX-2, inducible NOS, and NADPH oxidase. The transcriptional down-regulation of cytokines and other inflammatory markers in COX-1^-/- mice was mediated by a reduced activation of NF-B and signal transducer and activator of transcription 3. Administration of SC-560 prior to LPS injection also attenuated the neuroinflammatory response by decreasing brain levels of prostaglandin (PG)E₂, PGD₂, PGF₂, and thromboxane B₂, as well as the expression of proinflammatory cytokines and chemokine. These findings suggest that COX-1 plays a previously unrecognized role in neuroinflammatory damage.—Choi, S-H., Langenbach, R., Bosetti, F. Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury.