Aims: To evaluate and compare the effectiveness of periapical surgery using mineral trioxide aggregate (MTA) as a retrograde filling material with/without using hydroxyapatite or platelet-rich fibrin (PRF) in curetted periapical defect and to evaluate the patients clinically and radiographically at each recall visit. Subjects and Methods: The study was conducted on thirty patients having periapical radiolucency in maxillary anterior teeth. The selected teeth were divided into three groups: Group A, Group B, and Group C having 10 teeth each. All the teeth were treated with single visit root canal treatment. The periapical curettage along with apicoectomy was followed thereafter. In all the groups, root end cavity was prepared. In Group A, root end cavity was filled with MTA. In Group B, root end cavity was filled with MTA followed by placement of hydroxyapatite in the curetted periapical defect. In Group C, root end cavity was filled with MTA followed by placement of PRF in the curetted periapical defect. In all the three groups, patient recall visits were scheduled after 1, 3, 6, and 9 months time interval for clinical and radiological examination. Results: A significantly higher rate of healing was observed after 9 months in Group C (82.36%) followed by Group B (65.16%) and Group A (60.12%). Conclusions: Placement of root end filling material contributes greatly to the success of surgical treatment. To enhance the healing of periapical defect, use of host modulating agents such as PRF is preferred over grafts as these are autologous and contain growth factors that promote faster healing of periapical defects.