Background: Tenecteplase is a genetically-modified variant of the tissue plasminogen activator alteplase, with increased fibrin-specificity, administered as a more convenient intravenous bolus. Recent data, from the AcT trial, have shown tenecteplase to be non-inferior to alteplase in patients with acute ischemic stroke (AIS) treated within 4.5 hours from symptom onset, the direction of effect favoring tenecteplase. As a result, the Heart and Stroke Foundation of Canada has added tenecteplase to the Stroke Best Practice Recommendations. However, its cost-effectiveness in the Canadian setting remains unknown. Methods: An analysis was performed to estimate the cost-effectiveness of tenecteplase compared to alteplase in the AIS population. The model structure combines a decision tree for the first 90 days post index stroke, where the 7 modified Rankin Scale (mRS) states are informed by the AcT trial, and a Markov model for the remainder of the lifetime horizon. Cost and utility values were derived from the literature and public sources. Canadian health care system and hospital perspectives were used. Results: This economic analysis demonstrates that tenecteplase is dominant compared to alteplase, providing more quality-adjusted life years at lower costs. Conclusions: Adding tenecteplase to hospital formularies for AIS would generate savings for the health care system while providing more benefits.