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Macrophages, a significant component of atherosclerotic plaques vulnerable to acute complications, can be pro-inflammatory (designated M1), regulatory (M2), lipid- (Mox) or Heme-induced (Mhem). We showed previously that low (LSS) and oscillatory (OSS) shear stress cause thin-cap fibroatheroma and stable smooth muscle cell-rich plaque formation respectively in ApoE-knockout (ApoE −/− ) mice. Here we investigated whether different shear stress conditions relate to specific changes in macrophage polarization and plaque morphology by applying a shear stress-altering cast to the carotid arteries of high fat-fed ApoE −/− mice. The M1 markers iNOS and IRF5 were highly expressed in macrophage-rich areas of LSS lesions compared to OSS lesions 6 weeks after cast placement, while the M2 marker Arginase-1, and Mox/Mhem markers HO-1 and CD163 were elevated in OSS lesions. Our data indicates shear stress could be an important determinant of macrophage polarization in atherosclerosis, with low shear promoting M1 programming. [ABSTRACT FROM AUTHOR]