It has been suggested that within the traditional body mass index (BMI) categories there is a heterogeneous pattern of cardiometabolic risk factor clustering. The objective of this research was to determine the associations among obesity, cardiometabolic abnormalities, and cardiovascular disease (CVD) in a large population-based study of Appalachian adults. The study comprised a cross-sectional survey of Appalachian adults residing in 6 communities in Ohio and West Virginia, who were aged 18 years and older (n=14,783, 50.9% women). The authors categorized BMI into normal weight (<25 kg/m2), overweight (25-29.9 kg/m2), and obese (≥30 kg/m2). Cardiometabolic abnormalities were defined as the presence of hypertension, elevated triglycerides (≥150 mg/dL), decreased high-density lipoprotein cholesterol (<40 mg/dL [men], <50 mg/dL [women]), elevated fasting glucose (≥100 mg/dL)/diabetes, insulin resistance (homeostasis model assessment >5.13), or elevated C-reactive protein (>3 mg/L). They found that 25.6% of normal-weight adults displayed clustering of ≥2 cardiometabolic abnormalities; in contrast, 36.8% of overweight/obese adults displayed no clustering. Compared with normal-weight persons without clustering of cardiometabolic abnormalities (referent), the odds ratio of CVD was 1.06 (95% confidence interval [CI], 0.84-1.34) among overweight/obese individuals without cardiometabolic clustering, 2.21 (95% CI, 1.74-2.81) among normal-weight individuals with cardiometabolic clustering, and 2.45 (95% CI, 2.02-2.97) among overweight/obese individuals with cardiometabolic clustering. These results suggest that within the traditional BMI categories, there may be heterogeneity of CVD risk depending on whether there is underlying clustering of cardiometabolic abnormalities.