Summary. Background: Severe stroke carries high rates of mortality and morbidity. The aims of this study were to determine the characteristics of patients who initially presented with severe ischemic stroke, and to identify acute and subacute predictors of favorable clinical outcome in these patients. Methods: An observational cohort study, Acute Stroke Registry and Analysis of Lausanne (ASTRAL), was analyzed, and all patients presenting with severe stroke – defined as a National Institute of Health Stroke Scale score of ≥ 20 on admission – were compared with all other patients. In a multivariate analysis, associations with demographic, clinical, pathophysiologic, metabolic and neuroimaging factors were determined. Furthermore, we analyzed predictors of favorable outcome (modified Rankin scale score of ≤ 3 at 3 months) in the subgroup of severe stroke patients. Results: Of 1915 consecutive patients, 243 (12.7%) presented with severe stroke. This was significantly associated with cardio-embolic stroke mechanism (odds ratio [OR] 1.74, 95% confidence interval [CI] 1.19–2.54), unknown stroke onset (OR 2.35, 95% CI 1.14–4.83), more neuroimaging signs of early ischemia (mostly computed tomography; OR 2.65, 95% CI 1.79–3.92), arterial occlusions on acute imaging (OR 27.01, 95% CI 11.5–62.9), fewer chronic radiologic infarcts (OR 0.43, 95% CI 0.26–0.72), lower hemoglobin concentration (OR 0.97, 95% CI 0.96–0.99), and higher white cell count (OR 1.05, 95% CI 1.00–1.11). In the 68 (28%) patients with favorable outcomes despite presenting with severe stroke, this was predicted by lower age (OR 0.94, 95% CI 0.92–0.97), preceding cerebrovascular events (OR 3.00, 95% CI 1.01–8.97), hypolipemic pretreatment (OR 3.82, 95% CI 1.34–10.90), lower acute temperature (OR 0.43, 95% CI 0.23–0.78), lower subacute glucose concentration (OR 0.74, 95% CI 0.56–0.97), and spontaneous or treatment-induced recanalization (OR 4.51, 95% CI 1.96–10.41). Conclusions: Severe stroke presentation is predicted by multiple clinical, radiologic and metabolic variables, several of which are modifiable. Predictors in the 28% of patients with favorable outcome despite presenting with severe stroke include hypolipemic pretreatment, lower acute temperature, lower glucose levels at 24 h, and arterial recanalization.