Background: Hepatic encephalopathy (HE) is a major neuropsychiatric complication caused by liver disease characterized by cognitive and motor dysfunction. The only curative treatment to date remains liver transplantation (LT). Historically, HE has always been considered to be a reversible metabolic disorder and has therefore been expected to completely resolve following LT. However, even following the implantation of a new liver, persisting neurological complications remain a common problem affecting as many as 47% (8 47%) of liver transplant recipients. LT is a major surgical procedure accompanied by intraoperative stress and confounding factors, including blood loss (hypovolumia) and hypotension. We hypothesize, in the setting of MHE, that the compromised brain becomes predisposed to what would normally be an innocuous hypotensive insult, resulting in cell injury and death. Methods: Six-week bile-duct ligated (BDL) rats with MHE and respective controls will be used. Blood is withdrawn from the femoral artery (inducing hypovolemia) until an arterial pressure of 30 mmHg (hypotension) and maintained for 150 minutes. Upon sacrifice, brains are perfused and extracted for apoptotic analysis (western blot) and neuronal cell count (immunohistochemistry). Results: Both BDL rats and SHAM-operated controls without hypotension do not display any neuronal loss. However, BDL rats following hypotension demonstrated a significant decrease in neuronal cell count in the frontal cortex using NeuN+DAPI and Cresyl Violet compared to hypotensive SHAM-operated controls. In addition, neuronal loss was associated with an increased in cellular stress protein, hsp32, hsp70 and caspase-3, suggesting apoptotic cell death. Discussion: These findings suggest that patients with MHE are more susceptible to hypotension-induced neuronal cell loss. Moreover, these results suggest a patient with HE (even MHE), with a “frail brain”, will fare worse during LT and consequently result in poor neurological outcome. The combination of MHE and hypotension may justify for the persisting neurological complications observed in a number of cirrhotic patients following LT. This implies the impact of MHE on outcome is undervalued. MHE should not to be ignored and patients with MHE merit to be treated pre-LT.