Background: High-alert medications are most likely to significantly harm the children when improperly used as, the consequence of an error with these medications are significantly worse for children. So, nurses should be aware about dealing with these medications safely. The study aim was to evaluate the effect of educational guidelines on nurses' performance about safe use of high alert medications at pediatric intensive care units. Study design: A quasi- experimental approach with pre and post intervention. Sample: A convenient sample of all available nurses (n=66) and purposive sample of children (n=66) at Pediatric Intensive Care Units in Benha University Hospital and Benha Specialized Pediatric Hospital. Tools of data collection: Tool (I): A structured interviewing questionnaire sheet: It consisted of Part A: Personal characteristics of studied sample that include: 1- The studied nurses, 2- Children, Part B: Nurses' knowledge regarding safe use of high alert medications. Tool II: An Observational Checklist used to assess nurses' practice about safe use of high alert medications. Tool III: Likert scale for nurses' attitude regarding safe use of high alert medications in children. Result: There was a highly statistically significance of studied nurses' knowledge, practice and attitude regarding safe use of high alert medications in PICU at pre and post educational guidelines phases (p<0.000). Conclusion: Implementation of educational guidelines strengthened nurses' performance regarding safe use of high alert medications. Recommendations: Establishing standardized guidelines for nurses regarding safe use of high alert medications that should be available in each hospital to enhance nurses' performance at PICU.