A number of diagnostic and management challenges exist for achieving complete regeneration of large through-and-through periapical lesions. An unfavorable endodontic outcome may occur as a result of uncontrolled infection or unpredictable bone healing. This article presents a case with a 15 × 15-mm through-and-through periapical lesion and persistent gingival swelling. Endodontic microsurgery and guided tissue regeneration were performed using a resorbable membrane and osseous substitute. A 2-year postoperative radiograph revealed complete resolution of the periapical radiolucency. Seven-year clinical and radiographic follow-up showed that the tooth was asymptomatic and a long-term successful outcome had been maintained. (Int J Periodontics Restorative Dent 2014;34:e1-e8. doi: 10.11607/prd.1472)