Isolated sphenoid sinusitis is often misdiagnosed because of its rarity and varied clinical presentation. Presentation is often both subtle and suggestive of other intracranial etiologic sites, as determined by the anatomic relationships of the sphenoid sinus. As well, the microbiology of acute sphenoid sinusitis has not yet been clearly defined. We present three cases of acute sphenoid sinusitis and a review of the English medical literature. We isolated Staphylococcus aureus in two of our three patients at the Hospital for Sick Children and also found it to be the predominant organism in 48% of positive cultures in the literature. All three patients presented were initially misdiagnosed, as were 78% of cases in the literature.