Atherosclerosis is the leading cause of heart attack and stroke worldwide. The key characteristic of atherosclerosis is accumulation of LDL cholesterol in artery walls, the subsequent infiltration by monocytes/macrophages, and the development of inflammation. Recently, we reported that plasma protein complement factor H-related 1 (FHR1) binds to the necrotic surfaces of cardiovascular plaques and induces inflammation. Moreover, the concentration of FHR1 is higher, whereas CFHR1 gene deletion frequency is significantly lower in patients with atherosclerosis in comparison to healthy controls. Here we generated muFHR1-/- (the murine homolog of FHR1) knockout mice and then crossed them with ApoE-/- knockout mice (a model of human hyperlipidemia). Notably, deletion of muFHR1 enhanced lipid conversion in the liver as evidenced by RNAseq analysis. This resulted in normalized cholesterol levels, reduced inflammation and plaque formation in muFHR1-/-ApoE-/- mice. These data suggest that muFHR1 directs uptake of oxLDL by macrophages, and supports foam cell formation, plaque development, and inflammation in dyslipidemic mice. As human FHR1 correlates with non-HDL cholesterol concentrations and inflammation markers in patients with atherosclerosis-associated cardiovascular disease (ACVD) we assume that FHR1 plays a key role in the development of atherosclerosis and subsequent events such as stroke and myocardial infarction.