Introduction: Occupational exposure to antineoplastic agents and safe handling of cytotoxic drugs (CDs) had gained a high concern among oncology nursing staff due to their potential health risks. Many organizations such as Occupational Safety and Health Administration (OSHA), Oncology Nursing Society and National Institute for Occupational Safety and Health (NIOSH) have recommended guidelines for safe handling of cytotoxic drugs. Aim of work: To assess the knowledge, attitudes, and practices (KAP) of oncology nursing staff working at Tanta University Hospitals towards the safe handling of CDs. Materials and methods: A cross-sectional study was conducted for 3 months (from February to April, 2018) at the Oncology department in Tanta University Hospitals, Egypt. A pre-designed questionnaire was used to assess nurses` KAP regarding safe handling of CDs. Results: A total of 55 oncology nurses participated in the study. The total KAP scores of nurses towards the safe handling of CDs were satisfactory among 63.6% of the studied group. The mean scores of responses for knowledge, attitudes, and practices were 19.05 ± 4.8 out of 26, 13.09 ± 3.07 out of 16, and 8.87 ± 1.35 out of 12, respectively. More than half of the nurses had previous training in the Oncology department. Defective use of personal protective equipments (PPE) during various steps of CDs handling was noticed. Conclusion: There was inadequate practice of safe handling of CDs and defective implementation of guidelines among the studied oncology nurses, necessitating more frequent in-service training and audit system to monitor and evaluate their performance after training.