Characteristics potentially associated with the development of wheeze symptoms were examined in a prospective cohort study of 624 middle-aged and older men who initially denied any history of wheezing or asthma. Initial evaluation included spirometry, methacholine challenge testing, allergy skin testing with common aeroallergens, serum total IgE concentration, blood leukocyte count, blood eosinophil count, and postural heart rate change (standing minus supine). The presence or absence of wheezing symptoms at follow-up 3 yr later was assessed by questionnaire. Multiple logistic regression was used to examine initial characteristics as predictors of subsequent wheezing. Current smoking was the strongest independent predictor of the new onset of wheezing (adjusted OR, 14.3; 95% confidence interval (CI), 3.9 to 52.3). The risk of developing new wheezing also increased with age (adjusted OR, 1.6; 95% CI, 0.9 to 2.9 comparing individual subjects 10 yr apart) and postural heart rate change at the initial examination (adjusted OR, 1.8; 95% CI, 1.1 to 3.0 comparing individual subjects differing by 10 beats/min). A significant association between greater methacholine airway responsiveness (PD20FEV1 < or = 16.8 mumol versus PD20FEV1 > 16.8 mumol) and the subsequent development of wheezing was observed among nonsmokers (adjusted OR, 5.2; 95% CI, 2.0 to 13.6) but not among current smokers. Other baseline variables were not independently related to the risk of developing wheezing symptoms. These data suggest that current smoking, age, nonspecific airway responsiveness, and altered autonomic function are independently related to the risk of developing wheezing symptoms in middle-aged and older men.