In case of a long-term periapical lesion, destruction of both vestibular and oral cortical plates is sometimes observed and even a through-and-through periapical lesion occurs. The success of the treatment decreases when an apicomarginal defect is added to the through-and-through periapical lesion. Large periapical lesions should be treated initially by orthograde root canal therapy. When the signs and symptoms of the infection don’t recede after the treatment, then surgical approaches should be considered. In this case report, a 22-year-old female with previously initiated therapy was referred for an endodontic microsurgery of tooth 22 (i.e., upper left lateral incisor). After the endodontic treatment the patient was referred to the oral surgeon for apicoectomy with augmentation of the bone defect. The sinus tract in the apex area of the tooth 22 remained active since the surgical intervention. Endodontic microsurgery and guided tissue regeneration were performed. The article presents diagnostic data, namely pre- and post-operative images of cone beam computed tomography (after 2 years), as well as pre-, intra- and post-operative clinical images. All pre- and intraoperative procedures and stages are detailed. In particular, separation of platelet-rich fibrin (PRF) from venous blood, retrograde preparation with an ultrasonic tip and a device using a dental operating microscope and the use of a collagen membrane. After two-year follow-up, radiographic examination revealed significant bone reconstruction and clinical signs and symptoms were absent. The patient hasn’t reported any symptoms since. The paper also analyzes scientific sources on the use of PRF and collagen membranes in bone defects of the jaws. Attention is also paid to the formation of a flap during operations of this type. The main six success factors in the treatment of such complex cases are highlighted. Rethinking the previously performed surgery (apicoectomy) in this patient, attention was paid to the main five factors that could contribute to the failure.