Isolated sphenoid sinusitis is an uncommon but potentially catastrophic infectious disease. The authors present 12 patients with acute, isolated sphenoid sinusitis and describe their presenting features and clinical courses. All patients experienced headache, facial pain, or both. Fever and leukocytosis were uncommon. Plain sinus radiographs and cranial computerized tomography scan were diagnostic. All patients were treated with antibiotics and recovered without infectious or neurological complications.