Although rodent studies indicate that atherosclerosis is a T(H)1-mediated disease and that atopic T(H)2 immunity is atheroprotective, findings in humans are conflicting. Total IgE (tIgE) is associated with atherosclerotic disease but has limited specificity for atopy. Our aim was to determine the relation between atopy, as indicated by a broad panel of serum allergen-specific IgE (sIgE), and past myocardial infarction (MI) in a sample representative of the US population. Data were analyzed from 4002 participants aged ≥ 20 years from the 2005-2006 National Health and Nutrition Examination Survey. Subjects reporting a history of MI had lower summed sIgE (5.51 vs 7.71 kU/L; P < .001) and were less likely to have ≥ 1 positive sIgE test (29.9% vs 44.6%; P = .02) or current hay fever (3.3% vs 7.6%; P = .002). After adjustment for age, sex, race/ethnicity, diabetes mellitus, hypertension, family history of MI, smoking, total/high-density lipoprotein cholesterol, body mass index, and C-reactive protein, the odds ratio (OR) for MI was 0.91 (95% CI, 0.85-0.97) per positive sIgE; 0.70 (95% CI, 0.57-0.85) per 2-fold increase in sum[sIgE]; and 0.82 (95% CI, 0.69-0.98) per 10% increase in the ratio of sum[sIgE] to tIgE. Analysis with 7 data-driven, prespecified allergen clusters found that house dust mite is the only allergen cluster for which sIgE is associated with reduced odds for MI (fully adjusted OR, 0.36; 95% CI, 0.20-0.64). Serum sIgE is inversely related to MI in the US population in a manner independent of multiple coronary risk factors.