INTRODUCTION: Systemic inflammation may affect the brain by aggravating the stage of encephalopathy and increasing intracranial pressure (ICP) especially if liver insufficiency with hyperammonemia is present. The aim of this study was to determine if the influence of concomitant hyperammonemia and lipopolysaccharide (LPS) on the brain can be prevented by dexamethasone and cyclooxygenase (COX) inhibitors. METHOD: Fifty-four male Wistar rats, 6 in each group, were divided into the following groups: Saline+ saline; LPS (2 mg/kg)+saline; LPS+indomethacin (10 mg/kg); LPS+diclofenac (10mg/kg); LPS+dexamethasone (2mg/kg) in experiment A. Experiment-B included the following groups: LPS+NH3 (140 μmol/kg/min)+saline; LPS+NH3+indomethacin; LPS+NH3+diclofenac and LPS+NH3+dexamethasone. ICP was monitored via a catheter placed in cisterna magna and changes in CBF were recorded by laser Doppler flowmetry. RESULTS: LPS with and without NH3 induced a similar increase in plasma 6-keto-prostaglandin-F1α (6-keto-PGF1α) concentration together with a concomitant rise in CBF and ICP. Indomethacin and diclofenac prevented the increase in ICP by LPS alone, and with the addition of NH3 the increase in both CBF and ICP, which was associated with a decrease in 6-keto-PGF1α. Dexamethasone only reduced the LPS induced increase in ICP but not CBF, and partly the 6-keto-PGF1α plasma concentration in the combined setup. CONCLUSION: These data indicate that activation of cycloooxygenases is of central importance for development of cerebral hyperemia and high ICP during concomitant systemic inflammation and hyperammonemia.