OBJECTIVE:: Atherosclerosis developed during premenopausal years predicts postmenopausal atherosclerosis burden. The objective of this study was to determine the effects of dietary soy protein isolate (SPI) and social status on atherogenesis and arterial gene expression in a premenopausal monkey model. DESIGN:: Socially housed premenopausal cynomolgus macaques (n = 84) were fed an atherogenic diet deriving protein from casein/lactalbumin or SPI (containing 1.88 mg isoflavones/g). After 36 months of diet consumption, iliac artery biopsies were assessed for atherosclerosis and expression of mRNA transcripts related to inflammation, macrophage and T-cell content, and estrogen receptors (ERs). RESULTS:: SPI reduced plaque size (P < 0.05), total plasma cholesterol, non-high-density lipoprotein cholesterol (HDLc), and the total plasma cholesterol/HDLc ratio (all P < 0.003), while increasing triglycerides (P < 0.006) and HDLc (P < 0.0001). Arterial mRNA for CD68 (P < 0.001), CD3 (P < 0.02), and CD4 (P < 0.001) and inflammatory markers monocyte chemotactic protein-1, intercellular adhesion molecule-1, and interleukin-6 (all P < 0.0001) were also lower in the group receiving SPI. For most outcomes, this effect remained even after adjustments for plaque size and plasma lipid concentrations. Arterial ER-alpha was inversely associated with atherosclerosis (P < 0.02) and increased with SPI (P < 0.001). Subordinate monkeys had lower ER-beta (P < 0.02) and higher interleukin-6 (P < 0.05) transcripts but did not differ from dominant monkeys in extent of atherosclerosis (P > 0.9). CONCLUSIONS:: Premenopausal consumption of SPI had plasma lipid-independent beneficial effects on the pathobiological processes involved in atherosclerotic plaque development, thus potentially establishing the basis for reduced postmenopausal complications. Dominant social status provided similar, albeit less extensive, benefits in risk markers.