Background/Aims: Hepatic encephalopathy (HE) is a neuro¬psychiatric syndrome 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 hypothesize that episodes of HE will accelerate neurological deterioration. Our goal was to evalu¬ate the impact of cumulative HE episodes on neurological 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 by injection of ammonium acetate starting week 3 post-BDL. 3 days following the last injection, neurological status was assessed. Upon sacrifice, brains were collected for western blot analysis of NeuN, SMI311, caspase-3, Bax/Bcl2 and GFAP. 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, cleaved-caspase-3 and Bax/Bcl2 protein expression were significantly increased, whereas NeuN and SMI311 were significantly decreased in hippocampus of episodic BDL 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 Bax/Bcl2 and a decrease in neuronal markers of NeuN and SMI311 in the hippocampus which suggests neuronal injury/loss. Elevated levels of GFAP in the hippocampus insinuates gliosis because of neuronal loss. These results suggest that multiple episodes of HE may cause permanent cell damage, leading to persisting neurological complications post-LT.