Isolated sphenoid sinus disease (ISSD) is an uncommon entity and may present with non-specific symptoms. As sphenoid sinus is located adjacent to vital structures, a diseased sphenoid sinus can potentially lead to devastating complications such as cranial neuropathies, cavernous sinus thrombosis and intracranial abscess. Herein, we report a case series of three patients who presented with different localization of headache as their main symptom.