Aims: Brain edema is a serious complication associated with hepatic encephalopathy (HE) due to chronic liver failure. It is unclear whether brain edema is of vasogenic (blood brain barrier (BBB) breakdown) or of cytotoxic (disturbance of neurocellular metabolism) origin. It has been demonstrated that the Na-K-Cl cotransporter (NKCC) located on the luminal side of the BBB is implicated in the pathogenesis of brain edema in different animal models of ischemia. Furthermore, following the administration of bumetanide, an inhibitor of NKCC, brain edema is attenuated. Therefore, our aim was to study the BBB integrity and the role of NKCC in the pathogenesis of brain edema in cirrhotic rats. Methods: Two distinct animal models of chronic liver failure and HE are used in the present study; 1) biliary cirrhosis model (6 weeks bile duct ligation (BDL)). 2) portacaval shunt model (4 weeks portacaval anastomosis (PCA)). Both models develop hyperammonemia however brain edema is only observed in BDL. BBB breakdown was assessed by measuring brain extravasation of BBB permeability tracers. Evans blue and sodium fluorescein were injected (i.v), brains were perfused and extravasation was determined by spectophotometry. Expression of BBB tight junction proteins (occludin, claudin-5, ZO-1 and ZO-2) were assessed by immunoblot. Bumetanide was administered (i.p) for 10 days in BDL and BDL SHAM. Brain water content was measured in the frontal cortex using the specific gravimetric method. Levels of brain NKCC mRNA were evaluated by RT-PCR in microvessels isolated using centrifugation methods. Results: Extravasation of Evans blue and sodium fluorescein was not detected and there was no significant change in all tight junction protein levels measured in both BDL and PCA (negative control) models. Brain water content was reduced in bumetanide-treated BDL rats compared to control (77.66±0.15% vs 78.12±0.21%). In brain microvessels, NKCC mRNA increased in BDL rats compared to BDL SHAM (0.78±0.09 vs. 1.92±0.42) whereas no change was found in PCA compared to PCA SHAM (1.72±0.52 vs. 1.53±0.23). Conclusions: BDL rats did not demonstrate a change in BBB integrity or a change in expression of BBB tight junction proteins. This suggests brain edema in BDL is not of vasogenic origin. Moreover, an increase of NKCC mRNA and an attenuation of brain edema following bumetanide treatment were demonstrated in BDL rats suggesting NKCC plays a role in the development of brain edema in chronic liver failure.