Background and Aims: Hepatic encephalo¬pathy (HE) is a neuro¬psychiatric syn¬drome and it is understood to be reversible following liver transplantation (LT). However, up to 47% of LT patients have been documented to have persisting neurological complications associated with a history of overt HE episodes. We hypo¬thesize that episodes of HE will accelerate neuro¬logical deterioration. Our goal was to evalu¬ate the impact of cumulative HE episodes on neuro¬logical status and brain injury in cirrhotic rats. Method: Five-week bile-duct ligation (BDL) rats, and Sham-operated controls were divided into episodic and non-episodic groups. Episodes of HE were induced every 4 days starting the week 3 post-BDL following injection of ammonium acetate. 3 days following the last injection, neurological status was assessed. Upon sacrifice brains were collected for western blot analysis; Neuronal nuclei (NeuN), caspase-3 and GFAP were measured. Results: Long-term memory (LTM) was impaired in both non- and episodic BDL groups vs respective controls and was further aggravated in episodic BDL rats. Both GFAP and caspase-3 protein expression were significantly increased, whereas NeuN was significantly decreased in hippocampus of episodic BDL rats vs non-episodic BDL rats. Conclusion: HE episodes exacerbates neurological impairments in BDL rats. LTM impairment was associated with an increase in caspase-3 and a decrease in NeuN in the hippocampus which suggests neuronal injury/loss. Elevated levels of GFAP in the hippocampus insinuates gliosis as a consequence of neuronal loss. These results suggest that multiple episodes of HE may cause permanent cell damage, leading to persisting neurological complications post-LT.