BACKGROUND AND PURPOSE: Anterior circulation large-vessel occlusion stroke, one of the most devastating stroke subtypes, is associated with substantial economic burden. We aimed to identify predictors of increased acute care hospitalization costs associated with anterior circulation large-vessel occlusion stroke. MATERIALS AND METHODS: Comprehensive cost-tracking software was used to calculate acute care hospitalization costs for patients with anterior circulation large-vessel occlusion stroke admitted July 2012 to October 2014. Patient demographics and stroke characteristics were analyzed, including final infarct volume on follow-up neuroimaging. Predictors of hospitalization costs were determined using multivariable linear regression including subgroup cost analyses by treatment technique (endovascular, IV tPA-only, and no reperfusion therapy) and sensitivity analyses incorporating patients initially excluded due to early withdrawal of care. RESULTS: Three hundred forty-one patients (median age, 69 years; interquartile range, 57- 80 years; median NIHSS score, 16; interquartile range, 13-21) were included in our primary analysis. Final infarct volume, parenchymal hematoma, baseline NIHSS score, ipsilateral carotid stenosis, age, and obstructive sleep apnea were significant predictors of acute care hospitalization costs. Final infarct volume alone accounted for 20.87% of the total cost variance. Additionally, final infarct volume was consistently the strongest predictor of increased cost in primary, subgroup, and sensitivity analyses. CONCLUSIONS: Final infarct volume was the strongest predictor of increased hospitalization costs in anterior circulation large-vessel occlusion stroke. Acute stroke therapies that reduce final infarct volume may not only improve clinical outcomes but may also prove cost-effective.