BACKGROUND: There is an inverse relationship between HDL cholesterol and coronary heart disease. Experimental studies have indicated that HDL cholesterol may exert an antiatherogenic effect by inducing regression of atherosclerotic plaques and by turning lipid-rich plaques into more fibrotic lesions. In this prospective, population-based ultrasound study, we investigated how HDL cholesterol relates to carotid plaque progression. METHODS AND RESULTS: The study included 1952 men and women aged 25 to 82 years who had at least 1 plaque present in the right carotid artery at baseline examination (1994). All plaque images were computer processed to yield a measure of plaque area in square millimeters and echogenicity, expressed as the gray-scale median. After 7 years of follow-up, a new ultrasound screening was performed, and the changes in plaque area and echogenicity were assessed. In a multivariable adjusted model, HDL cholesterol, age, systolic blood pressure, and current smoking were independent predictors of plaque growth. For a 1-SD (0.41 mmol/L) lower HDL cholesterol level, mean (SE) plaque area increased by 0.93 mm2 (0.44 mm2; P=0.03). When users of lipid-lowering drugs were excluded from analysis, the HDL estimate was strengthened (beta=1.46 mm2, P=0.002). Although plaque area increased in 70% of cases, and most plaques became more echogenic over the follow-up interval, the plaques that became more echolucent grew more in size than those that became more echogenic (P=0.002). CONCLUSIONS: This study shows that a high level of HDL cholesterol reduces plaque growth in subjects with preexisting carotid atherosclerosis. Transformation of the plaque mass into higher echogenicity is associated with reduced growth. Our findings may indicate that HDL cholesterol stabilizes plaques and counteracts their growth by reducing their lipid content and inflammation.