Antithrombotic therapy (AT) should generally be avoided within 24 hours after recombinant tissue-plasminogen activator (rt-PA) treatment but should be considered in patients with large-artery atherosclerosis (LAA) who undergo concomitant emergent endovascular treatment (EVT). The aim of the present study was to assess the safety of AT within 24 hours after rt-PA treatment in patients with hyperacute ischemic stroke due to LAA who received concomitant EVT. From January 2013 through July 2019, consecutive patients with acute ischemic cerebrovascular disease due to LAA who were admitted within 6 hours from symptom onset were recruited. The patients were classified into six groups based on the reperfusion treatment and early (within 24 hours) AT from rt-PA treatment. Safety outcomes were compared among the groups. A total of 155 patients (35 women [23%], median age 74 [IQR 66-79] years; NIHSS score 3 [1-10]) were included in the present study. Of these, 73 (47%) received no reperfusion therapy, 24 (15%) received rt-PA treatment and early AT, seven (6%) received rt-PA without early AT, 26 (17%) received EVT only, six (4%) received both rt-PA and EVT without early AT, and 19 (12%) received rt-PA and EVT with early AT. AT was administered a median of 3.9 (1.6-8.0) hours after rt-PA in patients with rt-PA+EVT with early AT. AT within 24 hours after rt-PA and EVT treatment did not increase hemorrhagic complications (p > 0.05 for all). In this retrospective analyses, early AT administration for patients with hyperacute stroke due to LAA treated with rt-PA plus EVT did not increase hemorrhagic events.