INTRODUCTION: National cholesterol treatment guidelines include a low level of high-density lipoprotein (HDL) cholesterol (<40 mg/dL) as a major risk factor for coronary heart disease (CHD) that should be considered when making decisions on treatment of low-density lipoprotein (LDL) cholesterol. METHODS:: We investigated the association of HDL and LDL-cholesterol with incident CHD events (fatal or nonfatal CHD) over 14 years of follow-up among 13,615 adults aged 45 to 64 years in the Atherosclerosis Risk in Communities study. RESULTS:: A total of 966 (7.1%) participants had a CHD event during follow-up. After adjustment for age, race, sex, diabetes, smoking, alcohol consumption, systolic blood pressure, waist circumference, chronic kidney disease and physical activity, a graded association was present between progressively lower levels of HDL-cholesterol and higher CHD risk, overall (P < 0.001) and within each level of LDL-cholesterol (<100, 100-129, 130-159, 160-189 and ≥ 190 mg/dL) investigated (all P < 0.05). In addition, after multivariable adjustment including LDL-cholesterol, each standard deviation higher HDL-cholesterol (18 mg/dL) was associated with a hazard ratio of incident CHD of 0.70 (95% CI: 0.63-0.77). CONCLUSIONS:: These data suggest a graded association exists between lower levels of HDL-cholesterol and CHD across the full range of LDL-cholesterol levels. As interventions targeting HDL levels are developed, the combinatorial effects of lower HDL levels with various levels of LDL-cholesterol should be examined. © 2011 Lippincott Williams & Wilkins.