Background Although low-density lipoprotein cholesterol (LDL-C) is recommended as the primary marker to guide lipid-lowering therapy, some data suggest non-high-density lipoprotein cholesterol (non-HDL-C) may better reflect coronary heart disease risk. Discordance between these measures has not been evaluated. Methods We used data from the National Health and Nutrition Examination Surveys 2005-2010 (n = 4986) to examine the discordance between these lipid parameters. Elevated levels of non-HDL-C and LDL-C were defined by using the 2004 Adult Treatment Panel III guidelines. Results The prevalence of high non-HDL-C and LDL-C was 22.7% and 24.5%, respectively. Of participants with high non-HDL-C, 9.7% had normal LDL-C, whereas 15.7% of participants with high LDL-C had normal non-HDL-C. We estimate 3.9 million US adults had high non-HDL-C and normal LDL-C, whereas 6.8 million US adults had high LDL-C and normal non-HDL-C. Persons with high non-HDL-C and normal LDL-C were older, more likely to be men, Hispanic, and have impaired fasting glucose, diabetes metabolic syndrome, and more risk factors for coronary heart disease. Conclusions Substantial discordance exists between high non-HDL-C and high LDL-C among US adults. Reliance on either single measure could result in failure to classify cardiovascular heart disease risks appropriately. © 2014 National Lipid Association. All rights reserved.