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Background: Hemoglobin (Hb) released by red blood cell lysis following intracerebral hemorrhage (ICH) causes neuroinflammation and cell death, inflicting irreversible brain damage. Haptoglobin (Hp) and CD163 form a scavenging system for Hb to protect tissues from its cytotoxic effects: Hp binds to Hb, and this complex is endocytosed by macrophages/microglia expressing the membrane receptor CD163. Currently, there is no effective treatment against ICH, and limited research exists on the respective functions of Hp and CD163 after ICH. This study aims to investigate the effects that Hp and CD163 have on outcomes after ICH in knockout animals.Methods: Automated striatal collagenase injection was used to induce ICH in wildtype (WT) control, CD163-/-, Hp-/-, and Hp-/-xCD163-/- mice. Functional motor outcomes were assessed at 24, 48 and 72h following ICH using neurological deficit scoring, open field locomotion, and accelerating rotarod. Animals were euthanized at 72h to measure anatomical outcomes through cresyl violet, Perl’s iron, and immunohistochemical staining.Results: Lesion volume, hematoma volume, and tissue injury in CD163-/- mice was 27.5+/-5.8% (p<0.0001), 30.6+/-4.6% (p=0.0021), and 23.0+/-4.1% (p=0.0041) smaller compared to WT, respectively. Lesion volume and tissue injury in Hp-/- mice was 28.2+/-7.2% (p=0.0006) and 29.5+/-2.5% (p=0.0011) smaller compared to WT, respectively. No significant differences in these measurements were detected between Hp-/-xCD163-/- and WT mice. Preliminary data for additional measures are as follow: Hp-/- mice had smaller hemispheric enlargement (an indicator of brain edema) and blood-brain barrier breakdown compared to WT mice, less iron and astrogliosis compared to WT and CD163-/- mice, and less induction of heme oxygenase compared to all other groups. The CD163-/- mice had less total Hb in brain tissue and less blood-brain barrier breakdown compared to WT mice. The Hp-/-xCD163-/- mice had less blood-brain barrier breakdown compared to WT mice.Conclusion: These initial findings demonstrate the differences in recovery following ICH. The outcomes of this preclinical study help in the design of future clinical trials to limit devastating brain damage following ICH.