Background: Brain edema is a serious complication associated with hepatic encephalopathy (HE) due to chronic liver failure (CLF) and its pathogenesis remains undefined. NKCC1, a Na-K-Cl cotransporter, located on the blood-brain barrier (BBB) has been demonstrated to be implicated in the pathogenesis of brain edema in experimental models of ischemia. Therefore, our aim was to 1) investigate the relationship of hyperammonemia, 2) study the integrity of the BBB and 3) determine the role of NKCC1, in association with brain edema in rats with CLF. Methods: Two distinct animal models of CLF and HE were used; i) biliary cirrhosis model (6 weeks bile duct ligation (BDL)) ii) portacaval shunt model (4 weeks portacaval anastomosis (PCA)). Brain water content was measured using the specific gravimetric method. BBB breakdown was assessed by measuring brain extravasation of injected BBB permeability tracers (Evans blue and sodium fluorescein). Expression of BBB tight junction proteins (occludin, claudin-5, ZO-1 and ZO-2) were assessed by immunoblot. Levels of brain NKCC1 mRNA were evaluated by RT-PCR in isolated cerebral microvessels. Rats were treated with bumetanide (an NKCC inhibitor; administered (i.p) for 10 days). Results: Similar degree of hyperammonemia was measured in both BDL and PCA rats however brain edema was only found in BDL rats. In brains of both BDL and PCA rats, extravasation of Evans blue and sodium fluorescein was not detected and no significant change in the levels of all tight junction proteins was found. Brain water content was reduced in bumetanide-treated BDL vs BDL-non treated (77.35±0.18% vs 78.89±0.25%). A 2.4 fold increase in NKCC1 mRNA was detected in BDL vs BDL-sham rats whereas no change was found in PCA vs PCA-sham rats. Conclusions: Chronic hyperammonemia independently does not lead to an increase in brain water. Brain edema, present in BDL rats, is not associated with a change in either BBB integrity or expression of BBB tight junction proteins and is therefore not of vasogenic origin. Furthermore, an increase in NKCC1 mRNA and attenuation of brain edema following bumetanide treatment, suggests NKCC1, independent of hyperammonemia, plays a role in the development of brain edema in CLF.