Introduction: Apixaban has been increasingly used over the past decade for the prevention of ischemic strokes in atrial fibrillation (AF) patients. Nonetheless, some patients may experience ischemic strokes despite apixaban therapy. There is scarce information about factors underlying apixaban failure in AF patients. Methods: A system wide search was employed at the Cleveland Clinic Health System using electronic records. All patients 18 years of age or older, who were diagnosed with AF, and developed an ischemic stroke while being treated with apixaban (January 2013 through May 2019) were included. A matched controls series (no stroke on apixaban) was included accounting for antiplatelet and statin therapy, and carotid artery disease. Multivariable analyses were performed to assess for associations between clinical characteristics and stroke on apixaban. Results: A total of 137 patients with stroke while on apixaban were identified and matched to 137 controls. Cases and controls were comparable in a large number of clinical characteristics. There was an association between apixaban dosing and risk of stroke. About 40% of the lower (2.5 mg BID) dose of apixaban was prescribed for patients who would have qualified for full dose. Being on inappropriately low dose of apixaban was associated with a higher risk of ischemic strokes compared to appropriately prescribed doses with an adjusted OR 3.37 [1.37-8.32]. Among appropriately prescribed doses, the 5 mg BID dose showed a statistically nonsignificant lower risk of ischemic stroke compared to the 2.5 mg BID dose, adjusted OR 0.55 [0.21-1.41]. Compared to the inappropriate use of the 2.5 mg dose, the appropriate prescription of the 2.5 mg dose was associated with a lower risk of stroke adjusted OR 0.34 [0.07-1.64]. Conclusion: In this series, there was a statistically significant association between being on an inappropriately low dose of apixaban and the odds of stroke while on apixaban therapy.