Background: High alert medications (HAM) are medications that have an increased risk of causing significant patient harm when used erroneously. Staff nurses should have adequate knowledge and practices to be able to manage HAM administration process in critical care units. Aim of the study: is to assess staff nurses' performance regarding to safety measures of high alert medications. Research design: A descriptive design was utilized. Setting: The study was conducted in critical care units at Suez Canal University Specialized Hospital in Ismailia. Subjects: The study sample included (96) staff nurses. Tools: Data were obtained through two main tools; Nurses knowledge regarding to safety measure of HAM self- administered questionnaire sheet and Nurses practice observational checklist. Results: about two thirds and three quarters (65.6%, 71.9%, 70.8% and 75%) of staff nurses had unsatisfactory level of knowledge regarding to HAM in relation to (precautions, actions should be taken when errors happen, dealing with other HAM and side effects) respectively. Around three quarters and less than two thirds (74% and 63.5%) of staff nurses had unsatisfactory level of practice pre and during administration respectively while more than one half (52.1%) of staff nurses had satisfactory level of practice post administration of HAM. Conclusion: it can be concluded that about two thirds of staff nurses had unsatisfactory level of knowledge and practice. There was highly statistical significant relation found between staff nurses' total level of knowledge and total level of practice. Recommendation: Offer educational programs and upgrading courses armed with evidence based guidelines based on staff nurses' needs to improve their knowledge and practice related to administration of HAM.