Purpose <p>Endoscopic endonasal treatment for petrous apex cholesterol granuloma (PACG) allows for natural drainage to the nasopharynx. The high postoperative recurrence rate of PACG is a problem, and a method of permanent drainage is desirable. A systematic review of the literature was conducted to investigate which techniques can achieve permanent drainage.</p> Methods <p>We report new symptomatic PACG cases treated by endonasal transsphenoidal marsupialization using a nasoseptal mucosal flap (NSMF). To verify the safety, efficacy, and long-term preventive effect on recurrence using an NSMF during endonasal transsphenoidal marsupialization, a systematic review of the literature was performed using the PubMed, Scopus, Embase, Wiley Online Library, and Cochrane Library databases.</p> Results <p>Over 5 years of follow-up, our two patients, who each developed hypoglossal nerve palsy and abducens nerve palsy, experienced maintained patency to the sphenoid sinus and complete recovery of their symptoms. The systematic literature review of endonasal transsphenoidal marsupialization for PACG revealed that the use of an NSMF was the most effective surgical procedure in select cases. The 5-year estimated recurrence-free survival rates were 46.0% in the simple drainage group, 80.7% in the drainage using stenting group, and 97.1% in the drainage using an NSMF group.</p> Conclusion <p>Transsphenoidal marsupialization using an NSMF may prevent recurrence or stenosis of the opened orifice of the PACG cavity, whereas simple drainage often leads to recurrence. However, more importantly, this approach should be limited to cases in which wide or safe fenestration to the sphenoid sinus can be performed.</p>