Vitamin K antagonists, mainly Warfarin, have been used for the prevention of stroke and systemic embolism among patients with Atrial fibrillation (AF). Patient comorbidities can increase the risk of stroke and mortality and reduce persistence due to medication burden. Guidelines recommend prolonged anticoagulation to prevent stroke. Inadequate persistence and early discontinuation remain a significant concern leading to suboptimal, outcomes. The objective of this study was to examine the persistence to Warfarin and to evaluate the predictors associated with non-persistence to Warfarin among patients with comorbid AF, diabetes, hypertension, and hyperlipidemia. This retrospective cohort study included patients enrolled in Texas Medicare Advantage Plan (MAP) with AF diagnosis between January 2016-December 2018 and a prescription claim for Warfarin between January 2019-December 2019. Patients were followed for 6 months after the index date. Patients were considered non-persistent if the prescription gap between two refills was more than 60 days. Logistic regression models were used to estimate the socio-demographic and clinical predictors associated with non-persistence. Among the 438 patients with AF, diabetes, hypertension, and hyperlipidemia, 93 patients had a prescription claim for Warfarin. A total of 70 (75.27%) patients were persistent to Warfarin at 180 days. Patients with low-income subsidy were significantly more likely to be non-persistent to Warfarin (OR 4.02; 95%CI 1.23-13.09; P=0.02). Patients with a prescription for proton pump inhibitor during baseline were less likely to be non-persistent to Warfarin (OR 0.17; 95%CI 0.03-0.88; P=0.03). Study findings reveal that one-fourth of patients were not persistent to Warfarin, indicating the necessity of an effective intervention to assist patients in improving medication persistence. Further research is needed to identify the barriers associated with non-persistence among patients with AF and multiple comorbidities to aid in the development of tailored interventions for improving long-term persistence.