Background Despite successful mechanical thrombectomy (MT), approximately 50% of patients with large vessel occlusion (LVO) stroke experience poor outcomes due to reperfusion injury. Intra-arterial infusion of human serum albumin (HSA) may offer neuroprotective benefits; however, its safety and feasibility have not been established when delivered via the internal carotid artery. In this study we aimed to evaluate the safety and technical feasibility of HSA infusion through the guiding catheter placed during MT in patients with anterior circulation LVO stroke following successful reperfusion.Methods We conducted a prospective, single-center, open-label, pilot trial evaluating intra-arterial infusion of 20% HSA immediately after MT in patients with anterior circulation LVO stroke. The study included a 3+3 dose-escalation and a dose-expansion phase. Eligible patients achieved successful reperfusion (modified Thrombolysis in Cerebral Infarction score >= 2b) and received HSA infusion via the guiding catheter. Safety endpoints included 90-day mortality, symptomatic intracranial hemorrhage (sICH), and serious adverse events. Post-hoc analyses explored infarct volume, immune markers, and proteomic/metabolomic signatures.Results Between September 2023 and February 2024, 42 patients received intra-arterial HSA infusion. In the dose-escalation phase (n=27), two deaths and two mild infusion-related adverse events occurred, with no sICH. In the dose-expansion phase (n=15), one death and one case of sICH were reported, with no HSA-related adverse events. Post-hoc analysis showed that the HSA group had a significantly smaller infarct volume at 24 hours compared with controls.Conclusions Intra-arterial infusion of 20% HSA in combination with MT is safe and feasible. Preliminary findings suggest a potential therapeutic benefit in reducing infarct volume.Trial registration number NCT05953623.