BACKGROUND Cholesteatoma of the paranasal sinuses is uncommon. Its clinical characteristics are an expanding growth of the affected paranasal sinuses consisting of keratinizing squamous epithelium with bony wall destruction. Among involved paranasal sinuses, sphenoid sinus cholesteatoma is the least common. METHODS An 82-year-old female diabetic patient presented with subacute onset of fever after experiencing chronic progressive headaches for more than 20 years. Nasal endoscopy found purulent discharge from left sphenoethmoidal recess. Computed tomography (CT) scan of the paranasal sinus showed soft tissue lesions that totally filled the left sphenoid sinus with posterior and inferior wall destruction. There was no evidence of connection to the left mastoid cavity. METHODS Left sphenoidotomy was performed. Histopathology revealed cholesteatoma. Two months after surgery, she became worse and CT showed extensive skull base destruction. The patient underwent bilateral sphenoidectomy and craniotomy with surgical debridement of osteomyelitis of the skull base. She received long-term intravenous ertapenam and sitafloxacin for treating drug-resistant Klebsiella infection. The osteomyelitis could not be controlled, and she died. CONCLUSIONS Progressive headache can be caused by an uncommon disease such as sphenoid sinus cholesteatoma, which is a surgical condition. Complicating osteomyelitis of the skull base requires extensive debridement surgery and should be anticipated.