Background: High Alert Medications are medications that are most likely to cause significant harm to the patient, even when used as intended. The HAMs included insulin, anticoagulants, sedatives, and opioids. Nurses' knowledge & performance about HAMs should be updated via in-service training and continuous educational programs to improve medications management process. Aim: Evaluate the effect of a training program on nurses' knowledge and performance in dealing with high alert medications. Setting: The present study was conducted at Alexandria Main University Hospital including three basic units' diabetes and metabolism, cardiovascular surgery, and oncology unit. Subjects: All the nurses available (40 nurses) who are giving direct care to patient (one group pre-test post-test). Tools: Two tools were developed to collect data. Tool I: Nurses' knowledge on dealing with HAMs structure interview schedule. Tool II: Nurses' skill competency level in dealing with HAMs observational checklist. Results: This study shows no statistically significant correlation between knowledge improvement and performance of the nurses in dealing with HAMs, at assessment phase (P= 0.317) then it became after implementation program immediately (P=0.206) and after three months it become (P= 0.235). Conclusion: Based on the current findings, it can be concluded the educational program was effective and there was improvement in nurses‟ knowledge and performance regarding high alert medications at immediate and after 3 months post program compared to preprogram phase. Recommendation: Continuous and mandatory in-service training for nurses who are dealing with this type of medications (preparation, storage, transferring, administration).