OBJECTIVES: Evaluate the short and long-term economic burden of acute ischemic stroke (AIS)/transient ischemic attack (TIA) in a real-world setting. METHODS: Patients in PharMetrics®, a large claims database of U.S managed care plans, with an initial hospitalization for AIS or TIA (inpatient ICD-9 codes; 433.x1, 434.01, 434.11, 434.91, 436.xx or 435.x) between 1995 and 2008 were included in the study. Medical care encounters, resource utilization, and hospital charges were extracted from healthcare claims. Mean total charges post-index stroke as well as charges for initial AIS/TIA hospitalization and re-hospitalizations for stroke, acute coronary syndrome (ACS), and peripheral artery disease (PAD) were computed for all patients. Multivariate models identified drivers of higher charges. RESULTS: A total of 163,493 AIS/TIA patients were identified [AIS: 110,105 (67.3%), TIA: 53,388 (32.7%)]. In univariate analyses, the mean initial hospitalization charge was $16,867 for TIA and $25,414 for AIS hospitalizations. While the greatest charges were accrued in the year post-index stroke ($57,937), patients experienced charges of at least $22,000 each year following initial hospitalization for 5 years. Among AIS/TIA patients, 57,142 (35%), 27,736 (17%), and 8,210 (5%) experienced a subsequent hospitalization for AIS, TIA, and hemorrhagic stroke with associated average hospitalization charges of $7,967, $8,649, and $16,611, respectively. Re-hospitalization for PAD and ACS occurred for 24,145 patients (14.8%), with average costs of $12,293 and $24,580, respectively. Multivariate analyses controlling for key covariates demonstrated that cardiac arrhythmia/atrial fibrillation, acute myocardial infarction, and hypertension were strongly associated with increased hospitalization charges for initial AIS/TIA hospitalization (p<0.0001). CONCLUSIONS: The economic burden of AIS/TIA is substantial; the costs are significant and continue over at least a five year period post AIS/TIA event. For patients with an initial AIS/TIA hospitalization, it is important to consider the economic implications of preventing hospitalizations for recurrent stroke as well as other atherothrombotic and cardioembolic events.