The independent association of individual allergen reactivity with respiratory disease was evaluated with use of the second National Health and Nutrition Examination Survey, a sample of the U.S. white civilian population, ages 6 to 24 years (n = 4295). Eight, 1:20 wt/vol, 50% glycerol, unstandardized extracts were administered by prick puncture. Allergen reactivity was reported as the percent with a mean erythema diameter 10.5 mm or greater at 20 minutes. Only the prevalence of asthma and allergic rhinitis increased with the increasing number of positive allergen skin tests. The independent association of individual allergen reactivity with respiratory disease was quantified with logistic models that included other allergen reactivity, age, sex, smoking, and region. Asthma was associated with reactivity to house dust (odds ratio, 2.9; 95% confidence interval [CI] 1.7 to 5) and Alternaria (odds ratio, 5.1; 95% CI: 2.9 to 8.9). Allergic rhinitis was associated with reactivity to ragweed (odds ratio, 2.3; 95% CI: 1.5 to 3.3); ryegrass (odds ratio, 2.8; 95% CI: 1.8 to 4.3); house dust (odds ratio, 2.5; 95% CI: 1.6 to 3.9); Alternaria (odds ratio, 2.3; 95% CI: 1.5 to 3.4). Asthma only (without allergic rhinitis) was associated with dust and Alternaria. Allergic rhinitis only (without asthma) was associated with ryegrass, ragweed, and house dust. When both asthma and allergic rhinitis were present, only house dust and Alternaria remained associated. These findings highlight the association of specific allergens with upper and lower respiratory diseases and the interactions among coexisting respiratory diseases.