Objectives To evaluate whether selective intra-arterial hypothermia during mechanical thrombectomy is associated with greater preservation of initially hypoperfused tissue in patients with anterior-circulation large-vessel occlusion. Methods This prospective single-center nonrandomized comparative cohort study included consecutive patients with anterior-circulation large-vessel occlusion treated with mechanical thrombectomy. Patients received selective intra-arterial hypothermia or standard treatment at the discretion of the treating interventionist after informed consent was obtained. The primary endpoint was hypoperfused tissue salvage volume, defined as baseline hypoperfusion volume on computed tomographic perfusion minus final infarct volume on follow-up magnetic resonance imaging. Secondary outcomes were analyzed descriptively without formal adjustment for multiple comparisons. Results Ninety-four patients were included, with 45 in the hypothermia group and 49 in the standard-treatment group. The prespecified primary endpoint, hypoperfused tissue salvage volume, did not differ significantly between groups: median hypoperfused tissue salvage volume was 107.85 mL (interquartile range, 53.80–159.64) in the hypothermia group and 81.96 mL (interquartile range, 50.23–143.80) in the standard-treatment group ( p = 0.384). In adjusted median regression, hypothermia was not significantly associated with tissue salvage volume (adjusted median difference, 21.08 mL; 95% confidence interval, −23.47 to 65.63; p = 0.350). Final infarct volume and safety outcomes did not differ significantly between groups. Descriptive secondary analyses showed nominally greater day-7 NIHSS improvement in the hypothermia group (6.2 ± 5.9 vs. 3.8 ± 5.7, p = 0.043), and a higher proportion of 90-day functional independence (82.2% vs. 61.2%, p = 0.039). Conclusion Selective intra-arterial hypothermia during mechanical thrombectomy was not associated with a significant improvement in hypoperfused tissue salvage volume, the prespecified primary endpoint. Nominally favorable secondary clinical signals should be interpreted as exploratory and require confirmation in larger, adequately powered randomized trials.