Background: Obesity has been linked with a chronic state of inflammation which may be involved in the development of metabolic syndrome, cardiovascular disease, non-alcoholic steatohepatitis, and even cancer. The objective of this study was to examine the association between obesity class and levels of inflammatory biomarkers from men and women who participated in the 1999-2004 National Health and Nutrition Examination Survey (NHANES). Methods: Serum concentrations of C-reactive protein (CRP) and fibrinogen were measured among US participants of the 1999-2004 NHANES. We examined biomarker levels across different weight classes with normal weight, overweight, and obesity classes 1, 2, and 3 were defined as BMI of <25.0, 25.0-29.9, 30.0-34.9, 35.0-39.9, and ≥40.0, respectively. Results: With CRP levels for normal weight individuals as a reference, CRP levels nearly doubled with each increase in weight class: +0.11 mg/dl (95% CI, 0.06-0.16) for overweight, +0.21 mg/dl (95% CI, 0.16-0.27) for obesity class 1, +0.43 mg/dl (95% CI, 0.26-0.61) for obesity class 2, and +0.73 mg/dl (95% CI, 0.55-0.90) for obesity class 3. With normal weight individuals as a reference, fibrinogen levels increase with increasing weight class and were highest for obesity class 3 individuals, +93.5 mg/dl (95% CI, 72.9-114.1). Individuals with hypertension or diabetes have higher levels of CRP and fibrinogen levels compared to individuals without hypertension or diabetes, even when stratified according to BMI. Conclusions: There is a direct association between increasing obesity class and the presence of obesity-related comorbidities such as diabetes and hypertension with high levels of inflammatory biomarkers.