BACKGROUND: Erythrolysis releases free Hb (hemoglobin), which is one of the most upstream and important molecules causing early brain injury and cerebral vasospasm after subarachnoid hemorrhage (SAH). The purpose of this study was to investigate if a Hb scavenger protein Hp (haptoglobin) supplementation prevents early brain injury and cerebral vasospasm and influences the lymphatic drainage mechanism in an established SAH model of mice by a blood injection into the prechiasmatic cistern. METHODS: This study consisted of 4 parts, with a total of 317 C57BL/6 male mice undergoing sham or SAH modeling, randomly followed by 24-hour intracerebroventricular infusion of no vehicle, 30.1 mg/mL BSA, 30.1 mg/mL Hp (100%; a mixture of Hp1-1, Hp2-1, and Hp2-2), 50% Hp, 25% Hp, and 12.5% Hp solutions from 30 minutes postmodeling. The effects were evaluated at 24 and 48 hours postmodeling. RESULTS: The 100%Hp decreased mortality and brain edema until 48 hours post-SAH and suppressed post-SAH neurological impairments, Hb infiltrations into the perivascular spaces and brain tissues, fibrinogen-positive microthrombi formation, microglial activation, and caspase-dependent neuronal apoptosis, as well as large-vessel vasospasm on India-ink angiography at 24 hours compared with vehicle-treated SAH mice. The Hp solutions up to 50% concentrations also prevented post-SAH neurological impairments, and those up to 25% concentrations suppressed post-SAH neuronal apoptosis and vasospasm development until 48 hours. Immunohistochemical staining of deep cervical and mandibular lymph nodes demonstrated that Hb was increased in the lymphatic sinus after SAH and was further increased by Hp administration in SAH animals. CONCLUSIONS: This study first showed that an Hp concentrate prevented early brain injury and cerebral vasospasm by inhibiting Hb penetration into brain tissues and increasing lymphatic drainage of free Hb in an established SAH model of mice.