MicroRNA-21 (miR-21) is an evolutionarily conserved microRNA, abundant in most cardiovascular tissues. It has been implicated in the pathogenesis of several cardiovascular diseases including restenosis, myocardial infarction, and heart failure. However, little is known about the contribution of miR-21 in atherosclerosis. My data show that expression of miR-21 is increased by >1.5-fold in murine atherosclerotic lesions and by 1.5-2.0-fold in the macrophages of Western diet (WD)-fed LDLR-KO mice (for 12-20 weeks). In vitro, LDL, oxidized LDL, acetylated LDL and LPS induced miR-21 by 2-4-fold and down-regulated its target protein, PDCD4, in bone marrow-derived macrophages. Basally, macrophages isolated from miR-21-KO mice showed induction of several cytokines and chemokines, and significantly increased early and late apoptosis. Stimulation of miR-21-KO macrophages with interferong+LPS polarized the macrophages to the pro-inflammatory M1 phenotype (increased expression of CD11c and CD86). LPS increased the nuclear translocation of NF-kB and increased the formation of several pro-inflammatory cytokines by 3-45-fold in miR-21-KO macrophages. Staurosporine and 4-hydroxynonenal increased both early and late apoptosis of miR-21-KO macrophages (2-4-fold). This was accompanied by increased cleavage of caspase-3, caspase-7, and caspase-9. Transplantation of bone marrow cells from miR-21-KO to LDLR-KO mice, followed by 12 weeks of WD, increased the lesion formation (1.7-fold), apoptosis (3-fold) and necrosis (1.6-fold) in the aortic valve of miR-21-KO chimeric mice. This was accompanied by increased staining for IL-1β, IL-12, cleaved caspase-3, and cleaved caspase-9 in the plaques of miR-21-KO chimeric mice. Collectively, these data suggest that miR-21 prevents atherosclerosis by inhibiting macrophage apoptosis, necrosis, and inflammation.