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Background— It is known that 5-lipoxygenase and its product, leukotriene B4 (LTB 4 ), are highly expressed in several human pathologies, including atherosclerotic plaque. LTB 4 signals primarily through its high-affinity G protein-coupled receptor BLT1, which is expressed on specific leukocyte subsets. BLT1 receptor expression and function on other atheroma-associated cell types is unknown. Methods and Results— To directly assess the role of the LTB 4 -BLT1 pathway in atherogenesis, we bred BLT1 −/− mice into the atherosclerosis-susceptible apoE −/− strain. Compound-deficient apoE −/− /Blt1 −/− mice fed a Western-type diet had a marked reduction in plaque formation compared with apoE −/− controls. Immunohistochemical analysis of atherosclerotic lesions in compound-deficient mice revealed a striking decrease in smooth muscle cells (SMCs) and significant decreases in macrophages and T cells. We report here novel evidence of the expression and function of BLT1 on vascular SMCs. LTB 4 triggered SMC chemotaxis, which was pertussis toxin sensitive in Blt1 +/+ SMCs and absent in Blt1 −/− cells, suggesting that BLT1 was the dominant receptor mediating effector functions through a G protein-coupled signaling pathway. Furthermore, BLT1 colocalized with SMCs in human atherosclerotic lesions. Conclusions— These new findings extend the role of inducible BLT1 to nonleukocyte populations and suggest an important target for intervention to modulate the response to vascular injury.