Background: Exchange transfusion (ET) is most the commonly done for neonates when the serum bilirubin level exceeds a level that puts the neonates at risk for central nervous system toxicity, this procedure life-saving intervention. Aim: was to evaluate the effect of instructional based nursing intervention program on nurses' performance of exchange transfusion for neonates. Method: A quasi-experimental (pretest/ posttest) research design was utilized in this study. Setting: The study was conducted in the neonatal intensive care unit (NICU) at Misr-ElHora and General Hospitals. Sample: A convenient sample was used in this research (45 nurses). Tools: Two tools: (1) Predesigned Questionnaire, (2) Observational checklists were used to collect data of the study. Results: Most of the nurses 84% had good knowledge while the highest number of the nurses 87% had competent practices in posttest. Moreover there were highly statistical significant positive correlation between total score level of nurses' knowledge as well as practices regarding exchange transfusion for the neonates. Conclusion: The current research's findings, it can be summarized that the most of the nurses had good knowledge while the high number of the nurses had competent practices in the post-test related the care of neonates undergoing exchange transfusion. Recommendations: Encourage nurses to enhance their knowledge as well as practices via attending training programs, conferences as well as workshops about care of neonates undergoing ET.