BACKGROUND AND PURPOSE: The purpose of the study was to evaluate the effect of APOE genotype and the feasibility of administering an apolipoprotein E-mimetic therapeutic to modify outcomes in a murine model of intracerebral hemorrhage. METHODS: Intracerebral hemorrhage was induced via stereotactic injection of 0.1 U Clostridial collagenase into the left basal ganglia of wild-type and apolipoprotein-E targeted-replacement mice, consisting of either homozygous 3/3 or 4/4 genotypes. Animals were randomized to receive either vehicle or apolipoprotein E-mimetic peptide. Outcomes included functional neurological tests (21-point neuroseverity score and Rotorod latency) over the initial 7 days after injury, radiographic and histological hemorrhage size at 3 and 7 days, brain water content for cerebral edema at 24 hours, and quantitative polymerase chain reaction for inflammatory markers at 6, 24, and 48 hours. RESULTS: Apolipoprotein-E targeted-replacement mice consisting of homozygous 3/3 demonstrated superior neuroseverity scores and Rotorod latencies over the first 3 days after intracerebral hemorrhage, decreased cerebral edema at 24 hours, and reduced upregulation of IL-6 and endothelial nitric oxide synthase at 6 hours when compared to their apolipoprotein-E targeted-replacement mice consisting of homozygous 4/4 counterparts. After intravenous administration of 1 mg/kg apolipoprotein E-mimetic peptide, both wild-type and apolipoprotein-E targeted-replacement mice consisting of homozygous 4/4 exhibited improved functional outcomes over 7 days after intracerebral hemorrhage, less edema at 24 hours, and reduced upregulation of IL-6 and endothelial nitric oxide synthase when compared to mice that did not receive the peptide. CONCLUSIONS: Our data indicate that APOE genotype influences neurological outcome after intracerebral hemorrhage in a murine model. In particular APOE4 is associated with poor functional outcome and increased cerebral edema. Additionally, this outcome can be modified by the addition of an apolipoprotein E mimetic-peptide, COG1410.