Rationale: A high-fat diet accompanied by hypertriglyceridemia increases an individual's risk for developing atherosclerosis. An early event in this process is monocyte recruitment through binding to VCAM-1 upregulated on inflamed arterial endothelium. Diets high in polyunsaturated fatty acids (PUFAs) may provide athero-protection by ameliorating this effect. Objective: We investigated the acute regulation of VCAM-1 expression in human aortic endothelial cells (HAEC) in response to triglyceride-rich lipoproteins (TGRL) isolated from subjects following consumption of a high-fat meal. Methods and Results: Postprandial TGRL isolated from 38 subjects were categorized as pro- or anti-atherogenic according to their capacity to alter the inflammatory response of HAEC. Pro-atherogenic TGRL increased expression of VCAM-1, ICAM-1, and E-selectin by ~20% compared to stimulation with TNF α alone, while anti-atherogenic TGRL decreased VCAM-1 expression by ~20% while still upregulating ICAM-1. The relative atherogenicity of TGRL positively correlated with particle density of TG, ApoCIII, ApoE, and cholesterol. Ω3-PUFA mimicked the effect of anti-atherogenic TGRL by down-regulating VCAM-1 expression. TGRL exerted this differential regulation of VCAM-1 by reciprocally modulating expression and activity of the transcription factor IRF-1 and expression of microRNA 126 (miR-126). Overexpression or silencing of IRF-1 or miR-126 expression recapitulated the pro- or anti-atherogenic regulation of VCAM-1. Conclusions: In response to a high-fat meal, TGRL bias the inflammatory response of endothelium via transcriptional and post-transcriptional editing of VCAM-1. Subjects with an anti-inflammatory response to a high-fat meal produced TGRL that was enriched in non-esterified fatty acids, decreased IRF-1 expression, increased miR-126 activity, and diminished monocyte arrest.