Protein Kinase C - epsilon (PKCɛ) is involved in diverse cellular processes such as migration, growth, differentiation, and survival. Public geneset analysis of human atherosclerotic plaque tissue revealed that PKCɛ expression is inversely correlated with plaque size and vulnerability. Similarly, peritoneal macrophages (MØ) from hypercholesterolemic mice have significantly lower PKCɛ expression. As MØ play a major role in atherogenesis, we generated a mouse strain with PKCɛ selectively deleted in the myeloid lineage (PKCɛ fl/fl LysMCre - mɛKO ). qPCR revealed no basal differences between genotypes in the expression of lipid uptake receptors, efflux transporters, or inflammatory markers. However, upon lipid loading, mɛKO MØs retained significantly more cholesterol than WT. Human-like hypercholesterolemia was induced in WT and mɛKO mice and assessed for lesion area and plaque morphology in aortic arches and aortic roots. We found that, compared to WT, the lesion area in mɛKO mice was significantly larger, more necrotic, had larger foam cells, and thinner collagen caps. These results demonstrate that loss of myeloid PKCɛ promotes atherosclerosis as determined by a variety of criteria. Together, these data identify myeloid PKCɛ as a novel atheroprotective gene, laying the foundation for mechanistic studies on the signaling networks responsible for the phenotype.