In this prospective study of patients with fulminant hepatic failure (FHF), we tested the hypothesis that arterial hyperammonemia results in cerebral accumulation of the osmotic active amino acids glutamine and alanine, processes that were expected to correlate with intracranial pressure (ICP). By using in vivo brain microdialysis technique together with ICP monitoring in 17 FHF patients (10 females/7 males; median age 49 (range 18 to 66) years), we found that arterial ammonia concentration correlated to brain content of glutamine (r=0.47; P<0.05) but not to alanine. A persisting high arterial ammonia concentration (above 200 micromol/L) characterized patients who developed high ICP (n=8) while patients who did not experience surges of increased ICP (n=9) had a decline in the ammonia level (P<0.05). Moreover, brain glutamine and alanine concentrations were higher at baseline and increased further in patients who developed intracranial hypertension compared with patients who experienced no surges of high ICP. Brain glutamine concentration increased 32% from baseline to 6536 (697 to 9712) micromol/L (P<0.05), and alanine 44% from baseline to 104 (81 to 381) micromol/L (P<0.05). Brain concentration of glutamine (r=0.59, P<0.05), but not alanine, correlated to ICP. Also arterial ammonia concentration correlated to ICP (r=0.73, P<0.01). To conclude, this study shows that persistence of arterial hyperammonemia is associated with profound changes in the cerebral concentration of glutamine and alanine. The elevation of brain glutamine concentration correlated to ICP in patients with FHF.