Background: Hepatic encephalopathy (HE) is a frequent and severe complication of liver disease with poor patient outcomes, the hyperammonemia is a key factor in the pathogenesis of it. HE reduces the patient's quality of life and increase caregiver's overload. Nurses have a critical role in prevention of complications and it is important to study their level of knowledge, practice, and attitudes. This study aimed to assess nurses' performance regarding management of patient with Hepatic encephalopathy at endemic care unites. A descriptive study was utilized to meet the aim of this study. Data were collected from Medicine intensive care units and Endemic ICU at Zagazig University Hospitals. A convenience sample of all available nurses who working in the above mentioned setting. Four tools were used, an interview questionnaire, observational checklist, nurses' attitude likert scale, and factors affecting nurses’ performance questionnaire. Results: this study revealed that only 14.0% and 24.0% of the studied nurses had satisfactory knowledge and practice level respectively regarding management of patient with HE, while 86% and 76.0% of nurses had unsatisfactory level. As well, 66.0% of the studied nurses had a positive attitude regarding management of patients with HE, while 34.0% of nurses had a negative attitude. 90.0% of the studied nurses reported that there performance was affected by nurse, patient, and work related factors. Conclusion: this study concluded that the majority of the studied nurses have unsatisfactory total knowledge level as well as more than three quarters of them had unsatisfactory total practice level, while two thirds of studied nurses had a positive attitude regarding management of patients with HE. Also, the most of the studied nurses their performance was affected by nurse, patient, and work related factors. Recommendation: the nurses working in the study settings in need for more training to improve their performance regarding management of patients with HE.