Background: Cysteinyl leukotrienes are pro-inflammatory mediators with a clinically established role in asthma and a potential human genetic and preclinical role in cardiovascular diseases. Given that cardiovascular disease has a critical inflammatory component, the use of a leukotriene antagonist may represent an innovative therapy to target inflammation in cardiovascular prevention. Methods: We performed an observational retrospective (three years) study on eight hundred asthmatic patients 18 years or older in Albania, equally classified in two cohorts, exposed or non-exposed to montelukast, matched by age and gender. Patients with a previous history of myocardial infarction or ischemic stroke were excluded. Results: we considered eight hundred asthmatic patients (368 male and 432 female) 18 years or older. Overall 37 (4.6%) of the asthmatic patients, 32 non-exposed and 5 exposed, suffered a major cardiovascular event during the 3 years observation period. All the cardiovascular events occurred among patients with an increased cardiovascular risk. Thus, we used both a propensity score (PS) matching and a PS adjusted Cox model for analysis. In both analyses exposure to montelukast remained a significant protective factor for incident ischemic events (HR = 0.222; HR = 0.241, respectively), independently from gender. The event-free Kaplan-Meier survival curves confirmed the lower cardiovascular incidence of patients exposed to montelukast (p = <0.0001). Conclusion: Collectively, our data indicates that there is a potential protective role of montelukast for incident ischemic events in the older asthmatic population, suggesting a co-morbidity benefit of montelukast in asthmatics and possible innovative therapy to target inflammation for cardiovascular prevention.