Background: There has been no large-scale trial comparing endovascular treatment (add-on EVT) after intravenous tissue plasminogen activator (IV tPA) and IV tPA alone in acute ischemic stroke (AIS) caused by internal carotid artery occlusion (ICAO). We aimed at investigating the effectiveness and safety of add-on EVT after IV tPA in AIS patients with ICAO. Methods: Between March 2010 and March 2013, 3,689 consecutive ischemic stroke patients who were hospitalized within 4.5 h of onset were identified using a prospective stroke registry at 11 centers in Korea. Among them, patients with persistent ICAO after receiving IV tPA and whose 3-month modified Rankin Scale (mRS) was available were finally enrolled. A propensity score analysis with inverse-probability of treatment weighting was used to eliminate baseline imbalances between those receiving add-on EVT and IV tPA alone. Results: Among 264 patients enrolled in this study (mean age 71.4; male 56.4%; median National Institute of Health Stroke Scale score 15), 117 (44.3%) received add-on EVT. The add-on EVT group had a higher frequency of favorable outcome on the mRS ≤2 (35.0 vs. 18.4%; adjusted OR (aOR) 2.79; 95% CI 1.66-4.67) and lower mortality (17.9 vs. 35.4%; aOR 0.24; 95% CI 0.13-0.42) at 3 months, when compared to the IV tPA-alone group. Add-on EVT did not significantly increase the risk of symptomatic hemorrhage (5.1 vs. 4.1%; aOR 1.01; 95% CI 0.37-2.70). The rate of successful recanalization (thrombolysis in cerebral infarction grade ≥2b) in the add-on EVT group was 69.2%. Conclusions: Compared to an IV tPA alone, add-on EVT can improve clinical outcomes in patients with symptomatic ICAO within 4.5 h of onset without a significant increase of symptomatic hemorrhage.