Objective: Diabetes, hypertension, hyperlipidemia, and overweight/obesity often cluster together. The prevalence of these cardiometabolic risk factor clusters (CMRFCs) is increasing significantly for all sociodemographic groups, but little is known about their economic impact. Research Methods and Procedures: The nationally representative Medical Expenditure Panel Survey was used (2000 and 2002). The current study estimated the national cost of CMRFCs independent of the cost of cardiovascular disease in the U.S., as well as the cost for all major payers and the marginal cost per individual using a Heckman selection model with Smearing retransformation. CMRFCs included BMI ≥ 25 and two of the following three: diabetes, hyperlipidemia, and/or hypertension. All amounts are expressed in 2005 $U.S. Results: National medical expenditures attributable to CMRFCs in the U.S. totaled $80 billion, of which $27 billion was spent on prescription drugs. Private insurance paid the largest amount of the national bill ($28 billion), followed by Medicare ($11 billion), Medicaid ($6 billion), and the Veterans Administration ($4 billion), whereas individuals paid $28 billion out-of-pocket. For each individual with CMRFCs, $5477 in medical expenditures was attributable to CMRFCs, of which $1832 was for prescription drugs. On average, individuals with CMRFCs spent $1668 out-of-pocket, of which $830 was for prescription drugs. Discussion: The results of this study show that CMRFCs result in significant medical cost in the U.S. independent of the cost of cardiovascular disease. Individuals, private insurers, Medicare, Medicaid, the Veterans Administration, and other payers all share this burden. Copyright © 2007 NAASO.