Background: The relationship of serum antigen-specific immunoglobulin E (IgE) with cardiovascular diseases (CVDs) remains poorly understood. This study aimed to explore the association of antigen-specific and total IgE with CVDs using data derived from the National Health and Nutrition Examination Survey (NHANES) 2005-2006. Methods and Results: The association of serum total or antigen-specific IgE levels with CVDs was analyzed by survey-weighted logistic regression modeling, adjusted by age, sex, race, education, body mass index, blood pressure, total cholesterol, C-reactive protein, homocysteine, diabetes, smoking, and alcohol consumption. 4953 subjects were included. Coronary heart disease was significantly related to serum total IgE levels. The association of serum total IgE levels with coronary heart disease was further validated by negative, >= 1 and 1-6 positive antigen-specific IgE. Myocardial infarction was positively associated with serum total IgE levels only when all antigen-specific IgE were negative, but inversely associated with serum total IgE when plant-specific IgE test results were positive. More specifically, myocardial infarction was also inversely related to positive oak, birch, or peanut-specific IgE. In addition, serum total IgE are positively associated with angina when at least one specific IgE were positive. Conclusions: Serum antigen-specific IgE, as well as total IgE, is significantly associated with CVDs independently of a long list of established cardiovascular risk factors, which is more informative than total IgE per se.