We hypothesized that knowledge of cerebral autoregulation (CA) status during recanalization therapies could guide further studies aimed at neuroprotection targeting penumbral tissue, especially in patients that do not respond to therapy. Thus, we assessed CA status of patients with acute ischemic stroke (AIS) during intravenous r-tPA therapy and associated CA with response to therapy. AIS patients eligible for intravenous r-tPA therapy were recruited. Cerebral blood flow velocities (transcranial Doppler) from middle cerebral artery and blood pressure (Finometer) were recorded to calculate the autoregulation index (ARI, as surrogate for CA). National Institute of Health Stroke Score was assessed and used to define responders to therapy (improvement of ≥ 4 points on NIHSS measured 24-48 h after therapy). CA was considered impaired if ARI < 4. In 38 patients studied, compared to responders, non-responders had significantly lower ARI values (affected hemisphere: 5.0 vs. 3.6; unaffected hemisphere: 5.4 vs. 4.4, p = 0.03) and more likely to have impaired CA (32% vs. 62%, p = 0.02) during thrombolysis. In conclusion, CA during thrombolysis was impaired in patients who did not respond to therapy. this variable should be investigated as a predictor of the response to therapy and to subsequent neurological outcome. The key objective of current acute ischemic stroke (AIS) treatment is based on rapid blood flow restoration by thrombolysis, using intravenous recombinant tissue plasminogen activator (r-tPA), and/or mechanical arterial recanalization techniques 1-3. Several factors predict stroke outcome including age, initial stroke severity, arterial blood pressure (BP), site of occlusion, collaterals, and others 4,5. Nevertheless, complete or partial successful recanalization may not necessarily result in favorable outcome, with a number of predictors hypothesized 6,7. In particular, BP control may affect penumbral lesion size, with an optimal strategy still lacking evidence 8-10. Therapeutic BP manipulation may further impact on microvascular autoregulatory failure, as a consequence of an increase in lactate and free oxygen radicals in the occluded and/or reperfused tissues 11. Cerebral autoregulation (CA) refers to a set of physiological mechanisms that maintain the constancy of cerebral blood flow (CBF) despite wide variations in arterial BP. CA can be impaired within the first hours of ischemic stroke onset 11 ; as a consequence, BP control may be important for improving both the ischemic area in the brain and clinical outcome. Therefore, assessment of CA during recanalization therapy for AIS is relevant, and may influence future strategies for personalized BP control and associated neuroprotection. The aims of the present study were to assess CA status of responder and non-responder AIS patients to intravenous r-tPA during the therapy and after 24-48 h, and to test the hypothesis that CA during thrombolysis is associated with early response to therapy.