BACKGROUND:Dyslipidemia is a major contributor to the development of atherosclerosis and coronary disease. Its role in the etiology of atrial fibrillation (AF) is uncertain. METHODS AND RESULTS:We studied 7142 men and women from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study who did not have prevalent AF at baseline and were not on lipid-lowering medications. Total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides were measured using standard procedures. Incident AF during follow-up was identified from hospital discharge codes; review of medical charts; study electrocardiograms; and, in MESA only, Medicare claims. Multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals of AF by clinical categories of blood lipids in each cohort. Study-specific results were meta-analyzed using inverse of variance weighting. During 9.6 years of mean follow-up, 480 AF cases were identified. In a combined analysis of multivariable-adjusted results from both cohorts, high levels of high-density lipoprotein cholesterol were associated with lower AF risk (hazard ratio 0.64, 95% CI 0.48 to 0.87 in those with levels ≥60 mg/dL versus <40 mg/dL), whereas high triglycerides were associated with higher risk of AF (hazard ratio 1.60, 95% CI 1.25 to 2.05 in those with levels ≥200 mg/dL versus <150 mg/dL). Total cholesterol and low-density lipoprotein cholesterol were not associated with the risk of AF. CONCLUSION:In these 2 community-based cohorts, high-density lipoprotein cholesterol and triglycerides but not low-density lipoprotein cholesterol or total cholesterol were associated with the risk of AF, accounting for other cardiometabolic risk factors.