OBJECTIVES: Thrombolysis for stroke has shown to be cost-effective despite its pharmaceutical high cost because the evolution of survivors to disability is reduced in a 30%.  Given its size, more than 100,000 by year, it is worthwhile an economic approach to understand the impact of its introduction at a population level in terms of budget of the Spanish health system and health gain. The objective of this study is to calculate the budget impact analysis of thrombolysis in Spain by means of a discrete event simulation model. METHODS: The budget impact analysis was based on the estimation of incidence of stroke and the prevalence of stroke-related disability in Spain from 2000 to 2015 and hospital and social costs. A discrete event simulation model was built to represent the flow of stroke patients in Spain from incidence to disability and death with and without thrombolysis. RESULTS: The prevalence of dependent patients would decrease from 150,236 to 146,172 if a 10% of stroke patients received thrombolytic treatment from 2000 to 2015. The first 5 years the cost of intervention surpasses the saved cost because of less dependent patients. The saved costs move ahead in 2005 and the gap with intervention costs grows till 2015. Benefit in effectiveness by year rises corresponds with a net gain of 156.6 in 2000 and 1360.2 QALYs in 2015. CONCLUSIONS: Thrombolysis impact onto the health and social budget entails a net benefit after five years and the gain in health grows continuously in correlation with the avoided dependent patients. On the other hand, the validation of the model enlightens the adequacy of the discrete event simulation approach to represent the epidemiology of stroke in order to calculate the budget impact analysis.