Hypertriglyceridemia (HTG), particularly in combined hyperlipidemia, increases risk for atherosclerotic cardiovascular disease, but the underlying mechanisms remain incompletely understood. We sought to determine contributions of circulating monocytes to atherosclerosis associated with HTG in combined hyperlipidemia, created by transgenic expression of human apoCIII in Ldlr-/- mice (Ldlr-/-ApoCIIItg) fed western high-fat diet (WD). Tissue culture with THP1 and primary human monocytes was used to examine effects of triglyceride (TG)-rich lipoproteins (TGRL) on monocytes. Ldlr-/-ApoCIIItg mice were also treated with apoCIII antisense oligonucleotide (ASO) and examined for foamy monocytes and atherosclerosis. Compared to Ldlr-/- mice, Ldlr-/-ApoCIIItg mice fed WD had early and persistent increases in lipid accumulation within monocytes and enhanced atherosclerosis. Ldlr-/-ApoCIIItg mice vs Ldlr-/- mice had higher levels of CD11c, CD36, and cytokines in foamy monocytes, with increases in foamy monocyte adhesion to VCAM-1 and oxLDL uptake. Monocytes took up TGRL in vivo and in vitro and changed phenotypes. Foamy monocytes infiltrated into atherosclerotic lesions, and specific and sustained depletion of CD11c+ (foamy) monocytes profoundly reduced atherosclerosis in Ldlr-/-ApoCIIItg mice on WD. Treatment with apoCIII ASO lowered plasma TG and cholesterol levels, improved foamy monocyte phenotypes, and reduced atherosclerosis in Ldlr-/-ApoCIIItg mice. In conclusion, HTG in combined hyperlipidemia accelerates atherosclerosis, in part, by increasing foamy monocyte formation and infiltration into atherosclerotic plaques. Treatment with apoCIII ASO is a potential new therapy for improving monocyte phenotypes and reducing atherosclerosis in combined hyperlipidemia.