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Diagnosis of isolated sphenoid lesions. Isolated lesions of the sphenoid sinus are rare, and diagnosis is difficult because of the non-specific symptoms and clinical signs. The pathology of these lesions can be divided into three groups: inflammatory lesions, tumoural lesions, and a small group of so-called miscellaneous lesions. In a retrospective study, we evaluated the diagnosis and underlying pathology of 49 consecutive isolated sphenoid lesions all subjected to diagnostic and/or therapeutic endoscopic sinus surgery. The diagnosis of isolated sphenoid lesions based on clinical history and clinical examination, including nasal endoscopy, was not reliable because of the non-specific symptoms and clinical signs. A definitive diagnosis could be made only by radiological imaging and/or surgical exploration. The largest group of patients suffered from inflammatory lesions (29 patients), followed by tumoural lesions in 17 patients. Two patients had a sphenoidal cerebrospinal fluid leak, and one patient had a cholesterol granuloma. The outcome for patients who underwent a therapeutic endoscopic surgical procedure was favorable in 22% and perfect in 67%. There were no complications during or after endoscopic surgery.