Inflammation and the recruitment of monocytes into the artery wall are thought to be important aspects in the initiation and progression of atherosclerosis. The present study was designed to examine the effects of a rigorous diet and exercise intervention on plasma lipids and inflammatory and circulating adhesion molecules. Twenty postmenopausal women at risk for coronary artery disease (CAD) were placed on a high-fiber, low-fat diet, where food was provided ad libitum and daily aerobic exercise, primarily walking, was performed. In each subject, pre- and post-intervention fasting blood was drawn for serum lipid, insulin, glucose, C-reactive protein (CRP), serum amyloid A (SAA), interleukin-6 (IL-6) and both soluble (s) intracellular and vascular adhesion molecule (sICAM-1 and sVCAM-1) were measured. After 2 weeks, significant reductions in body mass index (BMI) (P <.001), glucose (P <.05), insulin (P <.01), all serum lipids, and total cholesterol (total-C):high-density lipoprotein-cholesterol (HDL-C) (P <.01). Reductions in homeostasis model assessment for insulin resistance (HOMA-IR) (P <.01), CRP (P <.01), SAA (P <.01) and sICAM-1 (P <.05) were noted, as well as an increase in the quantitative insulin sensitivity check index (P <.05). Reductions were also noted in 5 women not using hormone replacement therapy (HRT). No significant reductions were found in IL-6 or sVCAM-1 in response to the intervention. Overall, this intervention resulted in improved metabolic and lipid profiles, reduced inflammatory, and cell adhesion molecules in postmenopausal women in the absence of caloric restriction. The rapid improvements may reduce the risk of acute myocardial infarction (MI), and if sustained, these changes may mitigate the risk for atherosclerosis progression and its clinical consequences.