Knowledge and practice of nurses about surgical site infections (SSIs) are not well studied in Ethiopia. This paper contains findings about Northwest Ethiopian nurses' knowledge and practice regarding the prevention of SSIs. The main objective of the study was to assess knowledge, practice, and associated factors of nurses towards the prevention of SSIs. The study was done using a questionnaire survey on randomly selected 423 nurses who were working in referral hospitals during the study period. The study showed that more than half of the nurses who participated in the survey had inadequate knowledge about the prevention of SSIs. Moreover, more than half of them were practicing inappropriately. The most important associated factors include lack of training on evidence based guidelines and sociodemographic variables (age, year of service, educational status, etc.). Training of nurses with the up-to-date SSIs guidelines is recommended.