Background: Transient global amnesia (TGA) is a syndrome featuring acute anterograde amnesia as the most striking clinical symptom. Its etiology is still a matter of debate. Most neurological guidelines allow the diagnosis on the basis of clinical criteria only; a more extensive evaluation is recommended only for patients with “red flags” like severe headache, nausea or vomiting, or metabolic abnormalities. The aim of our study was to assess the frequency of a severe underlying disease or alternative diagnoses (mimics) in patients fulfilling the clinical criteria. Methods: We evaluated the medical records and the imaging data of an unselected consecutive cohort of patients with suspected TGA over a 7-year period. All patients were hospitalized and received a neurological workup including brain imaging, color-coded duplex sonography of the brain supplying arteries, electroencephalography, and laboratory studies of blood and (in selected cases) cerebrospinal fluid. Results: 163 patients with 166 episodes of suspected TGA were hospitalized (3 patients twice). After the workup, the diagnosis of TGA was confirmed in 148/166 (89.2%) episodes (“simple TGA”). Eighteen patients (10.8%) either had an alternative diagnosis or a severe comorbidity that was assumed to have had an impact on the occurrence of the amnestic episode (“complicated TGA/mimic”). The most important differential diagnosis was stroke (11 patients, 6.6% of all TGA suspects and 61.1% of the complicated TGA/mimic group). Other mimics were transient epileptic amnesia (2 patients) and steroid-induced delirium (1 patient). Important comorbidities that had not been obvious at the time of presentation were severe sleep apnea (2 patients), triptan overuse (1 patient), and an involuntary amlodipine intoxication during TGA. Conclusion: As approximately every tenth patient with suspected TGA either had an alternative diagnosis or a severe comorbidity, which had not been obvious at the time of admission, we consider in-patient treatment of all suspected TGA cases as appropriate, preferably in the setting of a stroke unit, as ischemic stroke was the by far most important diagnosis mimicking TGA.