BACKGROUND: Thrombolysis with intravenous recombinant tissue plasminogen activator (IV-tPA) has been associated with significant improvements in clinical outcomes when initiated within 3 h of symptom onset. Although adjunctive therapies for acute stroke have been developed, challenges remain in identifying appropriate patients and therapeutic end-point measurements. OBJECTIVE: To describe the use of transcranial Doppler (TCD) monitoring in the Emergency Department (ED) to guide the decision for advanced reperfusion strategies after failure of IV-tPA. CASE REPORT: A 75-year-old man presented to the ED within 50 min after the acute onset of right-sided hemiparesis and aphasia. After administration of IV-tPA, there was no immediate improvement in neurological symptoms. TCD performed in the ED demonstrated persistent left middle cerebral artery (MCA) occlusion. Based on this information, the patient received intra-arterial tPA followed by mechanical thrombectomy of the MCA occlusion, resulting in clinical improvement of the patient's right hemiparesis and aphasia. CONCLUSION: TCD is a feasible assessment tool for use in the ED to aid in diagnosis and to guide treatment decisions in patients with acute ischemic stroke, including those not responding to IV-tPA therapy.