The receptor for AGE (RAGE) is a key mediator in cerebral ischemia. Based on the evidence from animal studies and the presence of increased high mobility group box 1 protein (HMGB1, a RAGE ligand) in the serum of stroke patients, we hypothesized that soluble RAGE (sRAGE) increase in serum after ischemic and hemorrhagic stroke and that the levels decrease with patient improvement.We performed a longitudinal study of the acute changes of sRAGE levels in a series of 15 ischemic and hemorrhagic stroke patients at admission and over a period averaging 1 week and extending for up to more than a month in some of the cases. Serum sRAGE was measured by an enzyme-linked immunosorbent assay (R&D Systems Inc., Minneapolis, MN, USA).Serum sRAGE at admission were not significantly different between patients and healthy controls, p=0.17. Over the following days after the event, stroke patients displayed an increase of the serum levels of sRAGE, which at peak ranged between 26% and 296%, p>0.001. Similar changes are seen for both types of events, hemorrhagic and ischemic. sRAGE changes paralleled recovery and recurrence or aggravation of the episodes. Biological variability of sRAGE as measured daily in healthy subjects over 21 days showed a CV of only 8.9%.Our results provide for the first time a proof of principle that circulating sRAGE increase after ischemic and hemorrhagic stroke and may become candidate biomarkers to consider in larger studies exploring prognostic or follow-up value.