Ischemic stroke is one of the leading causes for mortality and disability globally. In Vietnam, there are 200,000 stroke cases annually, and the direct medical cost for each episode varied from 5 million to over 120 million dong. Nowadays, thrombolysis is one of the best treatment options for acute ischemic stroke. This study aimed to evaluate the cost-effectiveness of thrombolysis with Actilyse in treating first-time acute ischemic stroke in Vietnam, compared to non-Actilyse treatment. Methods: The study used a model-based approach, with the combination of decision tree and Markov model. Societal perspective with lifetime time horizon was used. Efficacy, costs and utility parameters were synthesized from Vietnamese and international literature, combining with Vietnamese clinicians opinion. Results: Treatment with Actilyse increases cost by 5,206,331 VND and 0.08 QALY, equivalent to ICER of 69,063,527 VND/QALY gained. One-way sensitivity analysis showed that cost parameters such as rehabilitation cost, drug cost, health insurance co-payment rate and efficacy parameters had the most impact. However, the conclusion about the cost-effectiveness of the intervention did not change. Conclusions: Acute ischemic stroke treatment with Actilyse in Vietnma is very cost-effective, increase patient’s quality of life, compared with non-Actilyse treatment, when using the willingness-to-pay threshold of 3GDP per QALY.