Atherosclerosis is characterized by the deposition of lipoproteins in the vessel wall leading to inflammatory response, neointimal thickening, and occlusive plaque. Emerging data suggests that the cell surface marker CD47 is upregulated in atherosclerotic lesions. CD47 produces a ‘don’t eat me’ signal that prevents efficient clearance of diseased vascular cells by phagocytes (a process referred to as ‘efferocytosis’), and it has been hypothesized that dysregulated CD47 may contribute to expansion of atherosclerotic lesions by allowing the accumulation of inflammatory debris in the necrotic core. Blockade of CD47 has been shown to reverse this defect in efferocytosis and attenuate atherosclerosis in mouse models. Here, we evaluated the efficacy of BRB-002, a novel hybrid protein biologic inhibitor of CD47, in a mouse model of atherosclerosis. Four-week-old apolipoprotein E-deficient (ApoE -/-) male mice were fed a high fat diet for 12 weeks during which they were treated with BRB-002 at 2.5 mg/kg, BRB-002 at 10 mg/kg, or IgG isotype control (10 mg/kg) three times a week. Animals were monitored by serial measurements of hematologic parameters, pharmacokinetics, and CD47 receptor occupancy. After 12 weeks, mice were injected with a cathepsin B fluorescent probe and then necropsied to examine their descending aortas. Probes of cathepsin B activity have been used to detect atherosclerotic lesions and shown to correlate with areas of active inflammation and plaque burden. BRB-002 was generally well tolerated in ApoE -/- mice with similar hemoglobin, hematocrit, and red blood cell count between groups. Evaluation of aortas by cathepsin B activity showed that animals treated with BRB-002 at both 2.5 mg/kg and 10 mg/kg dose groups showed significantly decreased cathepsin B activity compared to mice treated with isotype control. These results suggest that blocking CD47 with BRB-002 can attenuate inflammation and atherogenesis in mice.