Background:  Blood exchange is the second- line treatment for sever hyperbilirubinemia. It involves removing aliquots of the neonate blood and replacing with donor blood in order to remove abnormal blood components and circulate toxins whilst maintaining adequate circulating blood volume. Aim of the study: Was to improve nurses' performance regarding caring of neonates with hyperbilirubinemia undergoing blood exchange. Research design: A quasi-experimental design was utilized.  Settings: Neonatal Intensive Care Units at Benha University Hospital and Benha Specialized Pediatric Hospital Sample: A convenient sample of 80 nurses working in the previously mentioned settings and a purposive sample (43) of neonates with hyperbilirubinemia undergoing blood exchange. Tools: Tool I: A structured interviewing questionnaire sheet including the following parts; Part (1): Personal characteristics of the studied nurses. Part (2): Personal characteristics of neonates. Part (3): Nurses' knowledge assessment sheet. Tool II: Observational checklists. Results: There was a highly positive statistical correlation between total knowledge and total practices scores of the studied nurses pre and post-implementation of the educational program. Conclusion: The educational program was effective in improving nurses' knowledge and enhancing their practices regarding care of neonates with hyperbilirubinemia undergoing blood exchange. Recommendation: Periodical follow-up of nurses' knowledge and practices regarding care of neonates with hyperbilirubinemia undergoing blood exchange to detect the points of strength and weakness to act on.