Solitary involvement of the sphenoid sinus is a relatively uncommon entity. A series of 132 patients with isolated sphenoid disease accumulated over a 22-year period is reported. A retrospective chart review was performed with special attention to the patients’ presenting signs, symptoms, and radiographic findings. There were 80 patients with inflammatory disease, 38 with neoplasms, four with fibroosseous disorders, and 10 with traumatic and developmental lesions. The most common presenting symptom was headache, followed by visual changes and cranial nerve palsies. Cranial nerve abnormalities were encountered in 12% of the inflammatory cases, 60% of the benign tumors, and 57% of the malignant tumors. Radiographically, bone remodeling was associated with chronic inflammatory disease, especially mucoceles. Bone erosion was found principally with neoplastic disease, occurring rarely with mucoceles. Extension was associated with malignant tumors.