Background: The palliative care program considers most effective and important nursing role for improving the patients' quality of life. It has significant impact on patient's outcome. The aim of this study was to evaluate the effect of palliative care program on nurse's knowledge and practice regarding care of patients with End-Stage Renal disease at Zagazig University Hospitals Subjects and methods: Research design: A quasi experimental research design was used. Setting: The study was conducted in Hemodialysis Unit at Zagazig University Hospitals. Subject: all nurses working in Hemodialysis Unit (35) nurse and purposive sample of (35) patients with ESRD. Tools of data collection: First tool was an interviewing questionnaire sheet for patients. The second tool was an interviewing questionnaire sheet for nurses. The third tool was an observational checklist nurse's practice regarding palliative care for the most health problems for patients. Results revealed that the most common health problems are fatigue, GIT symptoms, itching and dyspnea. There were highly statistically significant relations in severity of them with mean score in pre-program as well as highly statistically significant relations in study phases were found in nurse's knowledge and their practice throughout program phases. Conclusion: palliative care program had a positive effect in improving nurse's knowledge and practice as well as improving patient outcome. Recommendations:-The importance of developing palliative care evidence –based program which should be available in all hospital to be followed by all nurses.