Pathologic conditions involving the sphenoid sinus alone are rare. A retrospective chart review was performed of 182 cases of isolated sphenoid sinus lesions seen at the Mayo Clinic between 1935 and 1998. There were 53 cases of sinusitis, 44 mucoceles, and 15 fungus-related cases (61.5%), and the rest of the cases were divided among numerous other pathologic entities. Symptoms, differential diagnosis, and various therapeutic modalities are discussed. We believe that these data will be useful to clinicians considering multiple pathologic possibilities when faced with a lesion involving the sphenoid sinus alone.