Computerized tomography (CT) or magnetic resonance imaging (MRI) is indispensable for diagnosing acute ischemic stroke (AIS) patients who are candidates for recombinant tissue plasminogen activator (rt-PA) therapies, but further investigation concerning appropriate selection of therapy following advanced imaging including perfusion imaging has not yet been done. The 2018 AHA guidelines have recommended not to perform excessive time-consuming imaging before rt-PA. Here we describe two cases in which reperfusion therapy was decided based on advanced imaging. The first case was a 70-year-old woman with complaints of total aphasia and right unilateral spatial neglect. Her MRI revealed no apparent high signal area in diffusion-weighted image (DWI), and her magnetic resonance angiography (MRA) showed no large vessel occlusion. Subsequent perfusion-weighted image (PWI) analysis showed a unilateral perfusion deficit in the left middle cerebral artery (MCA) region. The other case was an 88-year-old man with complaints of minor unilateral spatial neglect, right conjugate deviation of the eyes, and dysarthria. His MRI also revealed no apparent high signal area in DWI, and MRA showed slight stenosis in the right middle MCA. Subsequent PWI analysis showed a unilateral perfusion deficit in the right MCA region. In both cases, intravenous rt-PA therapy was administered after the diagnosis of AIS and the patients responded well to the reperfusion therapy. When DWI is performed too early, detecting the ischemic core and differentiating between a diagnosis of stroke and stroke mimics is sometimes difficult. Evaluation of perfusion abnormalities in acute cases can be performed quickly, as shown in these cases. Although rt-PA can be given just by non-contrast CT with no hemorrhage, advanced imaging may be an option to identify difficult-to-diagnose patients who require reperfusion therapy.