The goal of this article is to review a series of patients with persistent unilateral middle ear effusion (MEE) and to suggest a more contemporary diagnostic algorithm. The author conducted a retrospective chart review of adults with persistent unilateral MEE and normal findings on physical and nasopharyngoscopic examinations whose MEE was eventually found to be caused by a variety of occult skull base lesions. The study population was made up of 79 patients-52 women and 27 men, aged 21 to 83 (mean: 54.8) at presentation-who had been referred to an academic tertiary care medical center between July 1, 1988, and June 30, 2008. Follow-up ranged from 9 months to 19.5 years (mean: 8.7 yr). Of this group, 50 patients (63.3%) had a malignant tumor, 26 (32.9%) had a benign tumor, and 3 (3.8%) had an internal carotid artery aneurysm. Eustachian tube occlusion had been caused by diffuse invasion in 33 patients (41.8%), by intracranial pathology in 24 (30.4%), and by extracranial-infratemporal lesions in 22 (27.8%). Nasopharyngoscopy cannot identify a variety of rare skull base lesions that cause eustachian tube compression or tissue invasion that ultimately leads to MEE. Therefore, patients with unexplained persistent unilateral MEE should undergo coronal magnetic resonance imaging or computed tomography to look for any intra- or extracranial lesions before undergoing ventilation tube placement.