Monocyte infiltration and macrophage formation are pivotal steps in atherosclerosis and plaque vulnerability. Gremlin-1/Drm is crucial in embryo/organogenesis and has been shown to be expressed in the adult organism at sites of arterial injury and to inhibit monocyte migration. The purpose of the present study was to evaluate and characterize the role of Gremlin1 in atherosclerosis. Here we report that Gremlin1 is highly expressed primarily by monocytes/ macrophages in aortic atherosclerotic lesions of ApoE knock out mice and is secreted from activated monocytes and during macrophage development in vitro. Gremlin1 reduces macrophage formation by inhibiting macrophage migration inhibitory factor (MIF), a cytokine critically involved in atherosclerotic plaque progression and vulnerability. Gremlin1 binds with high affinity to MIF (KD=54 nM) as evidenced by surface plasmon resonance analysis and co-immunoprecipitation, and reduces MIF-induced release of tumor necrosis factor alpha (TNFα) from macrophages. Treatment of ApoE knock out mice with a dimeric recombinant fusion protein, mGremlin1Fc, but not with equimolar control Fc or inactivated mGremlin1 Fc, reduces TNFα expression, the content of monocytes/macrophages of atherosclerotic lesions and attenuates atheroprogression. The present data disclose Gremlin1 as an endogenous antagonist of MIF and define a role for Gremlin1/MIF interaction in atherosclerosis.