Background The National Health and Nutrition Examination Survey (NHANES) 2005-2006 was the first population-based study to investigate levels of serum total and allergen-specific IgE in the general US population. Objective We estimated the prevalence of allergy-related outcomes and examined relationships between serum IgE levels and these outcomes in a representative sample of the US population. Methods Data for this cross-sectional analysis were obtained from NHANES 2005-2006. Study subjects aged 6 years and older (n = 8086) had blood taken for measurement of total IgE and 19 specific IgE levels against common aeroallergens, including Alternaria alternata , Aspergillus fumigatus , Bermuda grass, birch, oak, ragweed, Russian thistle, rye grass, cat dander, cockroach, dog dander, dust mite ( Dermatophagoides farinae and Dermatophagoides pteronyssinus) , mouse and rat urine proteins, and selected foods (egg white, cow’s milk, peanut, and shrimp). Serum samples were analyzed for total and allergen-specific IgE by using the Pharmacia CAP System. Information on allergy-related outcomes and demographics was collected by questionnaire. Results In NHANES 2005-2006, 6.6% reported current hay fever, and 23.5% had current allergies. Allergy-related outcomes increased with increasing total IgE levels (adjusted odds ratios for a 10-fold increase in total IgE level of 1.86 95% CI, 1.44-2.41 for hay fever and 1.64 95% CI, 1.41-1.91 for allergies). Increased levels of plant-, pet-, and mold-specific IgE contributed independently to allergy-related symptoms. The greatest increase in odds was observed for hay fever and plant-specific IgE (adjusted odds ratio, 4.75; 95% CI, 3.83-5.88). Conclusion In the US population self-reported allergy symptoms are most consistently associated with increased levels of plant-, pet-, and mold-specific IgE.