Abstract Body (Do not enter title and authors here): Introduction: The CHADS2 and CHADS2VASc scoring systems are used to determine thromboprophylaxis indication in patients with atrial fibrillation (AF). While these scoring systems include multiple independent risk factors for the development of ischemic stroke, their overall predictive performance is poor when applied to cancer populations. Research Question: To identify whether cancer serves as an independent risk factor for ischemic stroke in AF. Methods: TriNetX, a global health research database, was utilized to identify AF patients with and without malignancy from 2015 to 2022, excluding patients with prior cerebrovascular disease. Propensity score matching was conducted to control for demographic variables, heart failure, type 2 diabetes, hypertension and anticoagulation. Propensity matching yielded two cohorts consisting of 45,339 patients each. Risk and survival analyses were then run at 3 months, 6 months, 1 year, and 5 years after the index event. The primary outcome was stroke and secondary outcomes were mortality and major bleeding events. Results: At 3 months, our study showed that the incidence of stroke was higher in patients with AF and malignancy when compared to AF alone, with an odds ratio (OR) of 2.773 (p < 0.001). A Kaplan-Meier curve analysis revealed a hazard ratio (HR) of 2.683 with a confidence interval of 2.564-2.807. These results were consistent at the 6-month, 1-year and 5-year intervals, with an OR of 2.737, 2.685 and 2.167, respectively (p-value <0.001), and an HR of 2.659, 2.628 and 2.267, respectively. The results also revealed higher rates of mortality among the AF and malignancy cohort, along with elevated major bleeding events across all intervals. Conclusion: Patients with malignancy had a significantly higher risk of stroke compared to patients without malignancy, despite controlling for other CHADS2 and CHADS2VASc variables. This defines malignancy as an independent risk factor with an HR of at least 2 across all intervals. Additionally, there was a higher incidence of mortality in patients with AF and malignancy. However, this cohort also had higher rates of major bleeding. Therefore, future studies should investigate incorporating malignancy into the CHADS2VASc score.