Intensive lifestyle changes have been shown to regress atherosclerosis, improve cardiovascular risk profiles, and decrease angina pectoris and cardiac events. We evaluated the influence of the Multisite Cardiac Lifestyle Intervention Program, an ongoing health insurance-covered lifestyle intervention conducted at our site, on endothelial function and inflammatory markers of atherosclerosis in this pilot study. Twenty-seven participants with coronary artery disease (CAD) and/or risk factors for CAD (nonsmokers, 14 men; mean age 56 years) were enrolled in the experimental group and asked to make changes in diet (10% calories from fat, plant based), engage in moderate exercise (3 hours/week), and practice stress management (1 hour/day). Twenty historically (age, gender, CAD, and CAD risk factors) matched participants were enrolled in the control group with usual standard of care. At baseline endothelium-dependent brachial artery flow-mediated dilatation (FMD) was performed in the 2 groups. Serum markers of inflammation, endothelial dysfunction, and angiogenesis were performed only in the experimental group. After 12 weeks, FMD had improved in the experimental group from a baseline of 4.23 ± 0.13 to 4.65 ± 0.15 mm, whereas in the control group it decreased from 4.62 ± 0.16 to 4.48 ± 0.17 mm. Changes were significantly different in favor of the experimental group (p <0.0001). Also, significant decreases occurred in C-reactive protein (from 2.07 ± 0.57 to 1.6 ± 0.43 mg/L, p = 0.03) and interleukin-6 (from 2.52 ± 0.62 to 1.23 ± 0.3 pg/ml, p = 0.02) after 12 weeks. Significant improvement in FMD, C-reactive protein, and interleukin-6 with intensive lifestyle changes in the experimental group suggests ≥1 potential mechanism underlying the clinical benefits seen in previous trials. © 2010 Elsevier Inc. All rights reserved.