Physical activity (PhA) prior to stroke has been associated with good outcomes after the ischemic insult, but there is scarce data on the involved molecular mechanisms. Methods: We studied consecutive acute ischemic stroke patients admitted to a single tertiary stroke center. Pre-stroke PhA was evaluated with the International Physical Activity Questionnaire (METS-minute/week). We studied several circulating angiogenic and neurogenic factors at different time-points: Vascular Endothelial Growth Factor (VEGF), Granulocyte Colony-Stimulating Factor (G-CSF) and Brain-Derived Neurotrophic Factor (BDNF) at admission, day 7, and at 3 months. We considered good functional outcome at 3 months (mRS = 2) as primary endpoint, and final infarct volume as secondary outcome. Results: We studied 83 patients with at least two time-point serum determinations (mean age 69.6 years, median NIHSS 17 at admission). Patients more physically active before stroke had a significantly higher increment of serum Vascular Endothelial Growth Factor (VEGF) at 7th day when compared to less active patients. This increment was an independent predictor of good functional outcome at 3 months and was associated with smaller infarct volume in multivariate analyses adjusted for relevant covariates. We did not find independent associations of G-CSF or BDNF levels neither with level of pre-stroke PhA nor with stroke outcomes. Conclusions: Although there are probably more molecular mechanisms by which physical activity exerts its beneficial effects in stroke outcomes, our observation regarding the potential role of VEGF is plausible and in line with previous experimental studies. Further research in this field is needed.

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