To explore the relationship between sensitization to inhalant allergens and adult asthma, we performed two nested case-control studies of men being followed in the VA Normative Aging Study. In Study A, 46 subjects (mean age, 61.2 +/- 8.1 yr) with symptoms of asthma and an abnormal methacholine challenge test (cases) were compared with 92 age- and smoking-history-matched subjects, who denied symptoms and had normal methacholine challenge tests (controls). The age of onset of wheezing symptoms for the cases was 49.0 +/- 15.7 yr. Serum IgE reactivity to the aeroallergens Der P 1 and 2, cat, ragweed, and mouse was compared in cases and controls. Cases were more likely to be sensitized to cat allergen (23.9% versus 4.4%, p < 0.001) than were controls. Prevalences of sensitization to Der p 1, Der p 2, ragweed, and mouse were low and similar in the two groups. In Study B, 33 cases who developed new onset airway hyperresponsiveness on methacholine challenge testing were compared with 66 age-matched controls who maintained normal methacholine challenge tests. Cases had a higher prevalence of serum IgE reactivity to cat allergen (18.2% versus 6.1%, p = 0.059) and Der p 2 (21.2% versus 10.6%, p = 0.153) measured in serum obtained 3 yr before the development of airway hyperresponsiveness. These results suggest that in older men, sensitization to cat allergen is associated with asthma and that sensitization predates airway hyperresponsiveness to methacholine.