Isolated sphenoid lesions are rare. It is likely that isolated sphenoid sinus disease is underreported for a number of reasons. First, the presenting symptoms are often nonspecific; second, the inaccessibility of the sinus precludes optimal physical examination; and third, before the advent of CT and MRI scanning, radiologic examination of the sinus was inadequate. Endoscopic evaluation and current imaging techniques with CT or MRI have contributed to an increase in diagnosis of these lesions. Twenty-one patients with isolated sphenoid lesions that I treated in a 4-year period are presented. The pathology was unilateral sphenoid sinusitis (8), sphenoid mucoceles (4), inflammatory sphenochoanal polyp (3), inverting papilloma (2), invasive pituitary adenoma (1), carcinoma (1), aspergilloma (1), and fibrous dysplasia (1). Endoscopic biopsy was carried out in 7 patients (33.3%). A precise diagnosis after endoscopy, biopsy, and imaging studies was established in all patients. Definitive treatment included an endoscopic sphenoidotomy in 15 (71.4%). Five patients (23.8%) were treated with other therapeutic modalities. One patient did not require any definitive treatment. The combined use of imaging techniques and diagnostic nasal endoscopy allows for an accurate diagnosis and enables minimally invasive techniques to be tailored to the patient's disease.