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, persisting neurological complications remain a common problem affecting as many as 47% of LT recipients. LT is a major surgical procedure accompanied by intraoperative stress and confounding factors, including blood loss and hypotension. We hypothesize, in the setting of minimal HE (MHE), the compromised brain becomes susceptible to hypotensive insults, resulting in cell injury and death. Methods: Six-week bile-duct ligated (BDL) rats with MHE and respective controls (SHAM) were used. Blood is withdrawn from the femoral artery (inducing hypovolemia) until an mean arterial pressure of 30 and 60 mmHg (hypotension) and maintained for 120 minutes. Cerebral blood flow (BCF) was assessed by injecting fluorescent microspheres (1x106 microspheres/ml) through the brachial artery. Upon sacrifice, brains were extracted for apoptotic analysis (western blot) and neuronal cell count (immunohistochemistry). In a separate group, BDL rats were treated for MHE with ornithine phenylacetate (OP; OCR-002) (1g/kg) for 3 weeks. Results: Both BDL rats and SHAM-operated controls without hypotension did not display any cell injury or neuronal loss. However, BDL rats following hypotension (30 and 60mmHg) 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. CBF decreased in BDL rats compared to SHAM and correlated with degree of hypotension insult. BDL rats treated with OP did not lead to neuronal cell death following hypotension. Discussion: These findings strongly suggest that cirrhotic 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 liver transplantation and consequently result in poor neurological outcome. Combination of MHE and hypotension may account for the persisting neurological complications observed in a number of cirrhotic patients following LT. Therefore, MHE, i) should not to be ignored and ii) deserves to be treated in order to reduce the risk of neurological complications occurring post-LT.