Background: Computed tomography perfusion (CTP)-estimated core volume is associated with functional outcomes in acute ischemic stroke. This relationship might differ among patients, depending on brain volume. Materials and Methods: We retrospectively included patients from the MR CLEAN Registry. Cerebrospinal fluid (CSF) and intracranial volume (ICV) were automatically segmented on NCCT. We defined the proportion of the ICV and total brain volume (TBV) affected by the ischemic core as ICVcore and TBVcore. Associations between the core volume, ICVcore, TBVcore, and functional outcome are reported per interquartile range (IQR). We calculated the area under the curve (AUC) to assess diagnostic accuracy. Results: In 200 patients, the median core volume was 13 (5–41) mL. Median ICV and TBV were 1377 (1283–1456) mL and 1108 (1020–1197) mL. Median ICVcore and TBVcore were 0.9 (0.4–2.8)% and 1.7 (0.5–3.6)%. Core volume (acOR per IQR 0.48 [95%CI 0.33–0.69]), ICVcore (acOR per IQR 0.50 [95%CI 0.35–0.69]), and TBVcore (acOR per IQR 0.41 95%CI 0.33–0.67]) showed a lower likelihood of achieving improved functional outcomes after 90 days. The AUC was 0.80 for the prediction of functional independence at 90 days for the CTP-estimated core volume, the ICVcore, and the TBVcore. Conclusion: Correcting the CTP-estimated core volume for the intracranial or total brain volume did not improve the association with functional outcomes in patients who underwent EVT.