Background: The adrenal glucocorticoid stress response in humans causes catabolism, increasing blood glucose and heart rate, and possibly potentiates ischaemic damage to neurons. These effects could induce secondary brain damage in acute stroke. Materials and Methods: This prospective study was based on a single determination of s-cortisol in 172 patients included within 24 h of stroke onset, 50% within 12 h of stroke onset. All patients were admitted to hospital within 6 h of stroke onset. We investigated the relations of s-cortisol to neurological deficit measured by Scandinavian Stroke Scale (SSS), lesion volume on CT-scan, blood glucose on admission, pulse rate, blood pressure, body temperature, deteriorating stroke, cytokines and cytokine receptors, and outcome. Results: In a multivariate logistic regression analysis, s-cortisol was independently related to death within 7 days of stroke onset, odds ratio (OR) Cortisol +100 nmol/l 1.9 (95% CI 1.01–3.8); serum-cortisol was, however, not a predictor of death or dependency within 3 months. S-cortisol correlated to SSS ( ρ=−0.45, p<0.001), body temperature ( ρ=0.27, p<0.001), pulse rate ( ρ=0.26, p<0.001), and lesion volume ( ρ=0.33, p<0.001). S-cortisol was related to the presence of insular damage. Conclusion: Acute stroke mortality related to increasing serum-cortisol levels. S-cortisol was associated with stroke severity and markers reflecting stroke severity.