Background: We evaluated the management, outcome and haemorrhagic risk in a cohort of ischaemic stroke patients with mild symptoms treated with intravenous tissue plasminogen activator (tPA) within the first 4.5 h. Methods: We analysed data from a prospective stroke thrombolysis registry. A total of 1,043 patients received tPA between 2010 and 2014 in the 5 stroke units of the RESUVAL stroke network (Rhône Valley, France). Among them, 170 patients had a National Institute of Health Stroke Scale (NIHSS) score ≤4 (minor group: MG) before tPA and 873 patients had a NIHSS score >4. Results: A high rate (77%) of excellent outcome (3-month-modified Rankin Scale score ≤1) was observed in the MG. No symptomatic intracerebral haemorrhage occurred and the rate of any haemorrhagic transformation was 5%. Fifty-four percent of the MG patients had visible arterial occlusion before tPA. Patients of the MG were less likely to be transported by Emergency Medical Services and to be directly admitted to the stroke unit or to imaging. Median delays from onset to admission, from admission to imaging and from onset to tPA were longer in the MG. Conclusion: Our data provided evidence of safety and suggested potential benefit of thrombolysis in patients with NIHSS score ≤4. A majority of these patients exhibited arterial occlusion before thrombolysis. Most often, patients with mild stroke are not given priority in terms of the mode of transport, direct admission to stroke unit and rapid imaging, resulting in an increased delay from onset to thrombolysis. Health system improvements are needed to provide all suspected stroke victims equal access to imaging and treatment on an emergency basis.