Introduction: Cardio-pulmonary resuscitation (CPR) is a series of life-saving operations which increases the chance of survival after cardiac arrest by increasing the blood flow in vital organs. The purpose of this study was to investigate the knowledge of medical residents about principles of CPR. Methods: 357 residents of different specialties in Mashhad University of Medical Sciences between March 2015 and March 2016 entered this study as an available sample (census). Two questionnaires of demographic information and a cardiopulmonary resuscitation questionnaire (approved by the American Heart Association (AHA2010), which assessed the familiarity of the residents with the principles and rules of CPR on a 20-point scale) were used. Results: The highest score of knowledge about CPR principles was seen in Cardiology, Emergency Medicine and Anesthesiology residents (12. 5, 12. 20, and 12. 05 respectively). Among the participants, only the Emergency Medicine and Cardiology residents had an increasing level of knowledge about the principles of CPR during the academic years, which was statistically significant (P value<0. 01). Residents in the fields of Neurology, Nuclear Medicine and Psychology had a significant decrease in knowledge about the principles of CPR during the academic years (P value <0. 01). Conclusion: Residents with the most exposure to patients with heart disease and cardiac arrest have a better knowledge of CPR principles. Also, the level of residents’ knowledge on the scientific principles of CPR in all medical fields was not favourable.