Astrocytes play an important role in the pathogenesis of hepatic encephalopathy (HE) and ammonia toxicity, whereas little is known about microglia and neuroinflammation under these conditions. We therefore studied the effects of ammonia on rat microglia in vitro and in vivo and analyzed markers of neuroinflammation inpost mortem brain tissue from cirrhotic patients with and without HE and non-cirrhotic controls. In cultured rat microglia, ammonia stimulated cell migration, induced oxidative stress and an upregulation of the microglial activation marker ionized calcium-binding adaptor molecule 1 (Iba-1). Upregulation of Iba-1 was also found in the cerebral cortex from acutely ammonia-intoxicated rats and in the cerebral cortex from cirrhotic patients with HE, but not from cirrhotic patients without HE. However, ammonia had no effect on microglial glutamate release, prostaglandin synthesis and mRNA levels of iNOS, cyclooxygenase-2 (COX-2) and the pro-inflammatory cytokines IL-1α/β, TNF-α or IL-6, whereas in cultured astrocytes ammonia induced the release of glutamate, prostaglandins and increased IL-1β mRNA. mRNA and protein expression of iNOS and COX-2 or mRNA expression of pro-inflammatory cytokines and chemokine monocyte chemoattractive protein 1 (MCP-1) in cerebral cortex from patients with liver cirrhosis and HE was not different from those found in cirrhotics without HE or non-cirrhotic control patients. The data suggest that microglia becomes activated in experimental hyperammonemia and HE in humans and may contribute to the generation of oxidative stress. However, HE in patients with liver cirrhosis is not associated with an upregulation of inflammatory cytokines in cerebral cortex, despite microglia activation.