Open heart Surgical Site Infection (SSI) is a life-threatening complication that occurs after cardiac surgery, it is associated with severe outcomes including exacerbation all of the following: hospitalization, healthcare costs, morbidity, and mortality. The present study aimed to assess nurses' knowledge, and performance regarding prevention of open heart surgery site infection. This conducted through a cross-sectional study design, on 77 nurses enrolled conveniently from Open Heart Surgery Unit, Mansoura University Hospitals, Egypt. Data was collected by using nurses' knowledge assessment self-administrated questionnaire and nurses' performance observational checklist. The main findings illustrated that 45.5% of nurses had poor total score level of knowledge (< 60.00 -69.99), and 41.6% of them had expert total score level of performance (75 -< 85%). The researcher concludes that less than half of nurses have poor total knowledge score, and more than three-fourths of them have total expert, and proficient performance scores levels regarding the prevention of open-heart SSI. Accordingly, the following are recommended: continuous on job education programs should be provided for all nurses to enhance their knowledge and performance about prevention of open heart SSI, as well, further research are needed to explore factors that contribute to nurses' adherence to preventive measures of open-heart SSI.