Objectives:To evaluate the treatment outcome of large periapical cystic lesions treated by combining two novel, conservative approaches, “SealBio” and “Surgical Fenestration”.Materials and Methods:Five cases (4M:1F, age range 14-38 years, mean age 24.5 years) of large periapical cystic lesions, diagnosed on clinical and radiographic examination, were included in the study. After informed consent, endodontic treatment was initiated; chemo-mechanical preparation and intra-canal dressing of calcium hydroxide was given. At the next sitting after one week, further disinfection root canals was done by “apical clearing”, “apical foramen widening” and irrigation. A cotton pellet was kept in the access cavity. After local anaesthesia, full thickness muco-periosteal flap was reflected and the thinned out bone was removed with bone rongers, a small piece of cystic lining was excised and the cystic cavity was copiously flushed with Betadine solution. The remaining cystic lining was gently curetted and the flap was sutured back. “SealBio” was performed after gentle irrigation with saline and intentional over instrumentation. A calcium sulphate based cement was pushed in the cervical third of the canal and the access opening was sealed with glass ionomer cement. Patient was prescribed antibiotics and anti-inflammatory drugs for 5 days and sutures were removed after 7 days. Patients were followed up clinically and radiographically at regular intervals.Conclusions:In this pilot study, treatment outcome after combined technique of “SealBio” and “Surgical fenestration” was found to be highly effective in healing of large periapical cystic lesions. It was simple to perform and very conservative treatment; it required minimal bone removal, obviated the need for complete cyst enucleation, apicectomy and retrograde filling.