A stress response consisting of elevated levels of cortisol and catecholamines is common after acute stroke. The plasma levels of natriuretic peptides are known to be elevated after ischemic stroke, but the relations of these neurohormonal systems in the acute phase of stroke and their impact on long-term prognosis have not been studied previously. A series of 51 consecutive patients (mean age 68±11years) with an ischemic first-ever stroke underwent a comprehensive clinical investigation, scoring of their neurologic deficit by Scandinavian Stroke Scale (SSS), Barthel Index (BI) and Modified Ranking Scale (MRS) as well as measurements of plasma cortisol, norepinephrine, epinephrine, ACTH and atrial (N-ANP) and brain (N-BNP) natriuretic peptides on the 2nd and 7th days after ischemic stroke. The patients were followed up for 44±21 months. Higher levels of cortisol, ACTH and natriuretic peptides were observed in the stroke patients who died (n=22) during the follow-up than in the stroke survivors. Cortisol levels associated significantly with the 2nd and 7th day N-ANP and N-BNP levels, catecholamine levels (r= 0.55- 0.94, p < 0.01 for all) and measures of neurologic deficit (r= 0.36 - -0.44, p < 0.05). High acute phase cortisol levels assessed either in the morning (RR=5.4, p < 0.05) or in the evening (RR=5.8, p < 0.05) predicted long-term mortality after stroke in multivariate analysis. Activation of the hypothalamus-pituitary-adrenal axis in ischemic stroke is associated with elevated levels of natriuretic peptides. High cortisol and natriuretic peptide values predict long-term mortality after ischemic stroke, suggesting that this profound neurohumoral disturbance is prognostically unfavourable.