Background: Patients who present with symptoms mimicking ischaemic stroke (IS), but have a different diagnosis, are known as stroke mimics (SM). The necessity for rapid administration of intravenous thrombolysis in patients with acute IS may lead to treatment of patients with conditions mimicking stroke. A variable proportion of patients with SM (1.4–14%) are currently treated with intravenous tissue plasminogen activator therapy (IV-tPA). The outcome of these patients is generally favourable and complications are rather infrequent. We aimed to determine the frequency, clinical features and prognosis of SM patients treated with IV-tPA in an experienced stroke centre. Methods: A prospective registry was assembled with patients treated with IV-tPA at our stroke unit from January 2004 to December 2011. We recorded age, gender, baseline National Institutes of Health Stroke Scale (NIHSS) score, treatment delay, vascular risk factors, clinical syndrome and aetiology. We retrospectively analysed the clinical characteristics of SM, safety (symptomatic intracranial haemorrhage and mortality) and outcome measures (modified Rankin Scale at 3 months, mRS) and compared them with IS patients. Results: 621 patients were treated with IV-tPA during the study period, 606 (97.5%) were IS and 15 (2.4%) were SM. The aetiology of SM was somatoform disorders (5), headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) syndrome (3), herpetic encephalitis (2), glial tumours (2), and migraine with aura, focal seizure and cortical vein thrombosis in single cases. SM were younger (72 ± 14 vs. 53.7 ± 16 years, p < 0.05), had a lower baseline deficit [NIHSS 13 (9–18) vs. 8 (5–10), p < 0.05], fewer vascular risk factors, and left hemisphere symptoms were predominant (80 vs. 52.4%, p < 0.05). Global aphasia without hemiparesis (GAWH) was the presenting symptom in 8 (54%) SM and 44 (7%) IS (p < 0.05). Multimodal computed tomography was performed in 3 SM patients and showed perfusion deficits in 2 of them. No intracranial haemorrhage or disability (functional outcome at 3 months, mRS >2) was recorded in any SM patient. Conclusions: The use of intravenous thrombolysis appears to be safe in our SM patients, and prognosis is universally favourable. Somatoform disorder and HaNDL syndrome were prominent causes, and GAWH the most common presentation. The safety of thrombolysis in SM suggests that delaying or withholding treatment may be inappropriate: the benefit of thrombolysis in case of IS may outweigh the risks of treating an SM. Further studies may assess the future role of multimodal computed tomography in the differential diagnosis between IS and SM.