Abstract Funding Acknowledgements Pfizer pharmaceutical corporation Background Diabetes is a known risk factor for thromboembolic events in patients with non-valvular atrial fibrillation (NVAF). Whether patients on insulin therapy are at an increased risk for stroke compered to patients treated solely by oral antidiabetic medications is not yet established. Aim To assess the risk of ischemic stroke and mortality in patients with NVAF and diabetes mellitus (DM) treated by insulin vs. oral antidiabetic treatment. Methods A prospective, historical cohort study based on the Clalit Health Services (CHS) electronic medical records database, including all individuals age ≥ 21 years with a first diagnosis of NVAF between January 2010 to December 2016 and a minimal follow-up period of 1 year. Patients were divided into two groups based on their diabetes therapy regiment (insulin vs. oral antidiabetic medications). Results Overall study population included 12,231 patients with AF and DM, of them 3510 (28.7%) had an insulin-requiring diabetes. The median age was 72.4 years (IQR 65-80) in the insulin- treated group and 75.2 (IQR 68-83) in the orally treated group, with a slight majority of women in both groups, 51.6% and 53.5% respectively. Patients in the insulin group had significantly higher co-morbidity rates including hypertension (HTN) (93.6% vs. 91.2%; p < 0.001), congestive heart failure (CHF) (38% vs. 22.2%%; p < 0.001), previous cerebrovascular accident/ transient ischemic attack (CVA/TIA) (23.1% vs.14.5%; p < 0.001) and vascular diseases (62.1% vs. 46.5%; p < 0.001). Moreover, patient on insulin therapy were significantly less treated with anticoagulation medications at baseline compered to patients not treated with insulin (38.9% vs. 46.6%; p < 0.001). The incidence of stroke per 100 person-years was 2.62 in the insulin-treated group and 2.02 in the oral-treated group. Although, diabetes patients on insulin therapy had a significantly increased risk for stroke compared to patients not treated with insulin in the univariate analysis (HR: 1.34; 95%CI: 1.13- 1.60), this association was not found to be significant after adjusting for confounding variables (HR: 1.17; 95%CI: 0.96- 1.41). The rate of mortality per 100 person-years was 19 in the insulin-treated group and 12.6 in the oral-treated group. The risk for overall mortality was significantly higher in the insulin-treated group compared to the non-insulin group (HR: 1.38; 95%CI: 1.29- 1.48), as found in the multivariate Cox model, adjusted for age, gender, Creatinine clearance, HTN, CHF , CVA/TIA, vascular diseases, duration of diabetes and use of anticoagulation therapy. Conclusion In this cohort of patients with newly diagnosed NVAF and DM, patients on insulin are at increased risk of all cause mortality and a have a trend of increased risk of stroke after accounting for other recognized risk factors for stroke and mortality in this population.