Microsomal prostaglandin E2 synthase-1 (mPGES-1) constitutes an essential player of inflammation and is involved in the pathogenesis of rheumatoid arthritis (RA). Platelets participate in the regulation of inflammatory processes by the release of pro-inflammatory mediators and platelet-derived microparticles (PMPs). However, the role of the inducible mPGES-1/PGE2 pathway on platelet functions has not been investigated. Here we report a significant impact of mPGES-1 on platelet functions during inflammation. Wild-type (WT) and mPGES-1-/- (KO) mice were stimulated with lipopolysaccharide (LPS) for 24 hours. Platelet counts and activation were assessed by flow cytometry analyzing CD62P - CD154 expression, PMPs number, platelet-leukocyte aggregates and platelet aggregation. The accumulation of platelets and fibrinogen in the liver was analyzed by immunofluorescent staining. In native platelets from WT and mPGES-1 KO mice, there were no differences among the investigated functions. After LPS treatment, the number of platelets were significantly decreased in WT mice, but not in KO. Platelet activation, platelet-leukocyte aggregates, and PMP numbers were all significantly lower in KO mice compared to WT after LPS-treatment. In addition, KO mice displayed a significant reduction in platelet aggregation ex vivo In the liver of LPS-stimulated WT and KO mice, there were no differences in platelet accumulation, although, the percentage of total vessel area in the KO liver was significantly lower compared to WT. Our results demonstrate that systemic inhibition of mPGES-1 prevents platelet activation, which should have important implications regarding the cardiovascular safety of mPGES-1 inhibitors.