The outcome of stroke patients is complex and multidimensional. We evaluated the impact of acute-phase variables, including clinical state, complications, resource use and interventions, on 6-month survival after first-ever stroke, taking into account baseline conditions exerting a possible effect on outcome. As part of a National Research Program, we performed a prospective observational study of acute stroke patients in four Italian Regions. Consecutive patients admitted for a period of 3 months to the emergency rooms of participating hospitals were included. A total of 1030 patients were enrolled (median age 76.0 years, 52.1% males). At 6 months, 816 (79.2%) were alive, and 164 (15.9%) deceased. Survival status at the 6-month follow-up was missing for 50 (4.9%). Neurological state in the acute phase was significantly worse in patients deceased at 6 months, who showed also higher frequency of acute-phase complications. Cox regression analysis adjusted for demographics, pre-stroke function, baseline diseases and risk factors, indicated as significant predictors of 6-month death altered consciousness (HR, 1.70; 95% CI, 1.14-2.53), total anterior circulation infarct (HR, 2.13; 95% CI, 1.44-3.15), hyperthermia (HR, 1.70; 95% CI, 1.18-2.45), pneumonia (HR, 1.76; 95% CI, 1.18-2.61), heart failure (HR, 2.87; 95% CI, 1.34-6.13) and nasogastric feeding (HR, 2.35; 95% CI, 1.53-3.60), while antiplatelet therapy during acute phase (HR, 0.56; 95% CI, 0.39-0.79), and early mobilisation (HR, 0.55; 95% CI, 0.36-0.84) significantly increased 6-month survival. In a prospective observational study, stroke severity and some acute-phase complications, potentially modifiable, significantly increased the risk of 6-month death, independently of baseline variables. Early mobilisation positively affected survival, highlighting the role of early rehabilitation after stroke.