The interrelationships between smoking history, objective markers of allergy and inflammation, and methacholine responsiveness were examined among 778 middle-aged and elderly men (age range 41 to 86 yr). Methacholine responsiveness was analyzed using dose-response slope to describe each subject's responsiveness. Current smokers were observed to have significantly greater total serum IgE concentration ([IgE]), blood total leukocyte count, and blood eosinophil count than nonsmokers. Current smokers with at least one positive skin test reaction to common aeroallergens displayed significantly greater methacholine dose-response slope than smokers with negative skin test results (p less than 0.01). Among nonsmokers, skin test positivity was associated with slightly but not significantly greater methacholine responsiveness. Among subjects with negative skin test results, smoking was not associated with greater methacholine responsiveness. Blood eosinophil count and serum total [IgE] displayed weak but statistically significant direct relationships to methacholine dose-response slope (p less than 0.01), and these relationships were not significantly modified by smoking status. In a multivariate model, the cigarette smoking/skin test positivity interaction, total serum [IgE], and blood eosinophil count displayed significant, independent relationships to methacholine dose-response slope, although only a small portion of the variance of dose-response slope was accounted for by these covariates. These data suggest that smoking and atopy may act synergistically to increase the degree of nonspecific airway responsiveness displayed by middle-aged and elderly individuals. Allergic airway inflammation, as reflected by total serum [IgE] and blood eosinophil count, may also influence nonspecific airway responsiveness in this age group.