Background: The most recent American Heart Association/American Stroke Association acute ischemic stroke guidelines recognize tenecteplase (TNK) as an alternative to alteplase (ALT) for acute ischemic stroke (AIS) treatment. TNK has a longer half-life, and is given as a single intravenous bolus compared to the complex and cumbersome ALT administration. A switch to TNK was implemented at our Comprehensive Stroke center (CSC) after a rigorous training of nurses and providers on May 1, 2021. We sought to evaluate the comparative performance of two thrombolytics over the period of last two years of ALT and first two years on TNK use. Methods: This was a retrospective review of prospectively collected database of consecutive AIS patients treated with ALT between May 2019 to April 2021 and those who received TNK from May 2021 to April 2023 at our CSC. Data samples were analyzed with respect to baseline patient characteristics, stroke severity, Door to Needle (DTN) time, 90 day Modified Rankin Scores (MRS), complications, and cost savings. Statistical analyzes were used for between group comparisons (SPSS). Results: A total of 115 patients were treated with ALT and 134 - with TNK. There were no significant differences in baseline characteristics or stroke severity between the groups (mean NIHSS of 10 for both). The mean DTN was 53.0 minutes for ALT and 41.5 minutes for TNK (p<0.001). There was a strong trend towards improved 90-day clinical outcomes for TNK-treated patients (mRS 2.5 vs 3.1, p=0.06). No significant differences in rates of symptomatic Intracerebral Hemorrhage (SICH) were observed between two groups (2.6% ALT vs 2.9% TNK). Estimated cost savings of TNK use over two year period were $75,102. Conclusion: Our real-world data suggests that intravenous TNK for AIS appears to be safe and may result in improved clinical outcomes and substantial cost savings compared to ALT.