INTRODUCTION: Metabolic syndrome is a powerful predictor of cardiovascular events independent of overt diabetes. Dietary restriction and weight loss modify metabolic syndrome components. This study addresses whether combination pharmacologic therapy focused on dyslipidemia provides additional benefit. METHODS: This study examines the effect of 1 year of gemfibrozil, niacin and cholestyramine therapy on a baseline of aggressive dietary and lifestyle intervention in 143 clinically stable, nondiabetic patients with coronary disease, randomized into a double-blind, placebo-controlled trial. RESULTS: Cohort characteristics included age 63 ± 7 years, 92% men, 43% with previous myocardial infarction, systolic blood pressure 139 ± 17 mm Hg, triglycerides 168 ± 81 mg/dL and high-density lipoprotein cholesterol 34 ± 6 mg/dL. The mean number of metabolic syndrome components decreased from 2.2 ± 0.9 to 1.5 ± 1.1, P < 0.001, and metabolic syndrome prevalence decreased from 38% to 18% (P < 0.001) for the entire cohort. In the lifestyle intervention and placebo group, the mean number of metabolic syndrome components decreased from 2.2 ± 0.9 to 1.9 ± 1.1 (P = 0.01), and prevalence of metabolic syndrome decreased from 44% to 30% (P = 0.15). A far more marked change was observed with lifestyle intervention and pharmacologic therapy: abnormal metabolic components decreased from 2.2 ± 0.9 to 1.0 ± 1.0 (P < 0.001), and prevalence of metabolic syndrome decreased from 32% to 6% (P < 0.001). CONCLUSIONS: The combination of gemfibrozil, niacin and cholestyramine has profound, beneficial effects on the components of metabolic syndrome. These benefits are additive to those seen with aggressive diet and lifestyle modification.