Sickle cell anemia (SCA) is a hemoglobinopathy resulting in both overt and silent strokes in the pediatric population. Multiple mechanisms including anemia, hypercoagulability, secondary moyamoya syndrome, paradoxical embolism, and platelet activation are implicated in the pathogenesis of stroke in SCA. Despite a paucity of literature on the safety or efficacy of antithrombotic therapies, these agents are used in patients with SCA for primary and secondary stroke prevention. This study examined the prevalence of antithrombotic usage in the SCA-Stroke arm of the Patent Foramen Ovale and Stroke (PFAST) study cohort. Approximately 46.5% (72/155) of patients report using antithrombotic medications. The frequency of antithrombotic medications increased with recurrent strokes: 39.6% (42/106) of patients were on antithrombotic medications after a single stroke, while 61.2% (30/49) of patients were on medications after a recurrent stroke. Within this population, 42.6% (66/155) were on antiplatelet medications, and only 4.5% (7/155) were on anticoagulants. Factors significantly associated with increased usage of antithrombotic therapy were the absence acute chest syndrome and higher baseline hemoglobin concentrations. While the majority of patients were taking antithrombotic therapies for secondary stroke prevention, a minority of patients were taking medications for other indications such as headache prophylaxis and prior venous sinus thrombosis. Given these current clinical practice patterns and prevalent use, further research is needed to define the role of antithrombotic agents in pediatric SCA. There appears to be clinical equipoise for the use of these agents in the SCA and pediatric stroke population.