Background: Accumulating evidence from randomized-controlled clinical trials (RCTs) suggest that tenecteplase may represent an effective treatment alternative to alteplase for acute ischemic stroke (AIS). In the present systematic review and meta-analysis we sought to compare the efficacy and safety outcomes of intravenous tenecteplase to intravenous alteplase administration for AIS patients with large vessel occlusions (LVO). Methods: We searched MEDLINE and Scopus for published RCTs providing outcomes of AIS with confirmed LVO receiving intravenous thrombolysis with either tenecteplase at different doses or alteplase at standard dose 0.9mg/kg. The primary outcome was the odds of modified Rankin Scale (mRS) score of 0-2 at 3 months. Results: We included 4 RCTs including a total of 433 patients. Patients with confirmed LVO receiving tenecteplase had higher odds of successful recanalization (OR=3.05, 95%CI: 1.73-5.40; Figure A), mRS scores of 0-2 [odds ratio (OR)=2.06, 95%CI: 1.15-3.69; Figure B], and functional improvement defined as 1-point decrease across all mRS grades (common OR=1.84, 95%CI: 1.18-2.87; Figure C) at 3 months compared to patients with confirmed LVO receiving alteplase. There was little or no heterogeneity between the results provided from included studies regarding the aforementioned outcomes (I ² ≤20%). No difference in the outcomes of early neurological improvement, symptomatic intracranial hemorrhage (ICH), any ICH and the rates of mRS 0-1 or all-cause mortality at 3 months were detected between patients with LVO receiving intravenous thrombolysis with either tenecteplase or alteplase. Conclusion: AIS patients with LVO receiving intravenous thrombolysis with tenecteplase have significantly better recanalization and clinical outcomes compared to patients receiving intravenous alteplase.