Isolated sphenoid sinus disease (ISSD) describes a wide spectrum of pathologies including inflammatory, vascular, bony dysplastic, and neoplastic diseases. The aim of this study was to assess the frequency with which a neoplastic process was diagnosed in patients of ISSD and patient management strategies. A retrospective analysis was conducted for all ISSD patients who underwent surgery between January 2005 and January 2014 at a tertiary center. The clinical characteristics, radiologic studies, operative findings, endoscopic surgical techniques, pathology results, and treatment outcomes of the patients were analyzed. In all, 42 patients (31 women and 11 men) were included in the study. Histopathologic examinations revealed that 10 patients (23.4%) had neoplasms (8 benign and 2 malignant), 19 (45.2%) had mucocele, 7 (16.7%) had fungal disease, and 6 (14.3%) had meningoencephalocele and cerebrospinal fluid leakage. With the exception of 2 patients with plasmacytoma, complete removal of the lesions was achieved in all patients using transnasal or transethmoidal endoscopic approaches, and no local recurrences were observed during the mean follow-up period of 42 months. More than one fifth of the patients with ISSD were diagnosed with neoplasms. The results indicated that endonasal endoscopic approaches could effectively help manage patients with ISSD lesions, including those that were neoplastic. It is clear that precaution during preoperative planning is imperative to avoid unexpected situations and complications that may put surgeons in a difficult position during surgery.