Background: The third stage of labor is a critical period, thus using high fidelity simulation to enhance intern students' competency through implementing the clinical guidelines for active management of the third stage of labor is essential for preventing its serious complications mainly postpartum hemorrhage. The aim of this study: Was to determine the effect of high fidelity simulation on intern students' competency regarding clinical guidelines for active management of the third stage of labor. Subjects and Method: The study was carried out at Objective Structure Clinical Examination (OSCE) skills laboratory at Faculty of Nursing, Tanta University. A convenient sample consists of 50 intern nursing students who were trained at labor unit, obstetric department, Tanta university hospital and fulfilling the inclusive criteria. Three tools were used to collect the data: Tool (I): A structured interview schedule included three parts: Part (a) Socio demographic characteristics of the intern nursing students, part (b) Intern students' knowledge regarding the third stage of labor, and part (c) Intern students' knowledge regarding clinical guidelines for active management of the third stage of labor. Tool (II): Intern students' practice observational checklist contained seven sequential steps of clinical guidelines for active management of the third stage of labor. Tool (III): Modified Self-Confidence Measurement Scale included 7 items that measured how confident intern nursing students felt about the skills they performed during simulation training program. Conclusion: Based on the findings of the present study, it can be concluded that high fidelity simulation training significantly improved the intern students' knowledge, practice as well as the self-confidence regarding clinical guidelines for active management of the third stage of labor. Therefore, the study recommended that providing pre-service and in-service training programs using high fidelity simulation especially for newly appointed intern nurses is crucial to improve their knowledge and practices as well as the self-confidence.