Isolated aspergillosis of the sphenoid sinus is a rare condition that is frequently diagnosed at a late stage because of its nonspecific and varying symptomatology. We report the case of a 75-year-old diabetic woman with a long history of retroorbital pain before she developed a subacute cavernous sinus syndrome. Neuroimaging including CT scan and MRI suggested a malignant tumor involving the sphenoid sinus but the diagnosis of aspergillosis was made intraoperatively and by histopathological examination. Soon after surgical drainage of the sphenoid sinus and systemic anti-fungal drug therapy, both retroorbital pain and cavernous sinus syndrome had completely resolved. This case emphasizes the fact that invasive isolated sphenoid sinus aspergillosis must be considered in the list of lesions causing sinus cavernous syndrome.