Apical periodontitis (AP) is defined as an inflammatory and destructive reaction of periapical tissues and a consequence of bacterial invasion to the dental pulp and root canal system. To avoid possible complications and undesirable repercussions of the surgical treatment of large AP, more conservative non-surgical approaches are endorsed. In the presented hopeless cases, a newly introduced modified combination of triple antibiotics, that is Penicillin G, metronidazole, and ciprofloxacin (PMC), was used as a long-term intracanal medication in the non-surgical endodontic retreatments of large AP. In the course of 10-month to 3-year follow-up, the large periapical lesions completely disappeared, and thorough bone healing was evident. Additionally, complete functionality of the involved teeth as well as other favourable treatment outcomes of the addressed cases showed that the long-term use of PMC, as a modified combination of antibiotics, in non-surgical endodontic retreatments may successfully resolve large AP. However, further investigations and well-designed controlled clinical trials are recommended.