Fungus ball (FB) is the most common form of extramucosal fungal rhinosinusitis involving one or more paranasal sinuses. The sphenoid sinus is an uncommon site of this disease. Here, we present our 20-year experience of managing isolated sphenoid sinus FB (SSFB). We retrospectively reviewed a series of 47 cases of isolated SSFB encountered between 1996 and 2015 with reference to the chronological incidence, demographics, clinical features, radiological findings, treatment modalities, and outcome. Recently, the number of patients with isolated SSFB has increased markedly. The mean age of the patients in this study was 63.1 years (range 26–84 years), and there was significant female predominance. The most common symptom was headache (72.3%), which was localised in various regions. On the other hand, nasal symptoms presented at a relatively low rate. On computed tomography, the most common findings were total opacification, calcification, and sclerosis of the bony walls. There was no significant difference in the presence of SSFB between the ipsilateral and contralateral sides of the nasal septal deviation and concha bullosa. Magnetic resonance imaging demonstrated an isointensity on T1-weighted images and marked hypointensity on T2-weighted images. Treatment consisted of endonasal endoscopic sphenoidotomy with complete removal of the FB. The prognosis was good, with no recurrence after a mean follow-up of 13.2 months. Isolated SSFB is a rare disease, but its prevalence is increasing. Although the clinical presentation is usually vague and nonspecific, SSFB should be considered in patients with unexplained headache, especially in elderly women. Endoscopic sphenoidotomy is a reliable treatment with low morbidity and recurrence rates.