BACKGROUND Inflammation and oxidative stress have been implicated in the pathogenesis of atrial fibrillation (AF). Lipid-lowering drugs, particularly statins and fibrates, possess antiinflammatory and antioxidant properties. OBJECTIVES The purpose of this study was to assess the impact of lipid-lowering drug use on AF prevalence in patients with reduced left ventricular ejection fraction (LVEF). METHODS Data were obtained from ADVANCENT(SM), a multicenter registry of patients with reduced LVEF (<= 40%). Demographic, clinical, and echocardiographic parameters were collected from interviews and medical records. Medications, including lipid-lowering drugs, were recorded. RESULTS Of the 25,268 patients, 71.3% had hyperlipidemia, and 66.8% were prescribed lipid-lowering drugs. AF prevalence was 25.1% in patients taking lipid-lowering drugs compared with 32.6% in untreated hyperlipidemic patients and 32.8% in patients without hyperlipidemia (P <.001 for both comparisons). In multivariable analysis, lipid-lowering drug use remained significantly associated with reduced odds of AF (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.64-0.74), and this effect was Larger than that of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (OR 0.85, 95% CI 0.79-0.92) or beta-blockers (OR 0.95, 95% CI 0.88-1.02). The beneficial impact of Lipid-lowering drugs on AF risk was independent of their effects on the Lipid profile. In patients in whom data on specific lipid-Lowering drugs were available, 92% of the patients undergoing Lipid-Lowering therapy received statins, and 98% received statins and/or fibrates. CONCLUSION Use of Lipid-Lowering drugs in patients with reduced LVEF is associated with a significant reduction in the prevalence of AF independent of the Lipid profile and other known arrhythmia risk factors. This effect is Larger than that of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or beta-blockers and may be the result of the antioxidant and anti-inflammatory effects of statins and fibrates.