Parental tobacco smoking is associated with lower airway function and an increased incidence of wheezy respiratory illnesses in infants. We evaluated in 76 healthy infants whether exposure to parental tobacco smoking was associated with airway hyperreactivity, which could contribute to lower airway function and the increased wheezy illnesses. Airway function was measured using the raised-volume rapid thoracic compression technique, and airway reactivity was assessed by methacholine challenge (0.015-10 mg/ml), which was stopped for a more than 30% decrease in forced expiratory flow (FEF)(75) or the final dose with a less than 30% decrease. Parental tobacco smoking was associated with lower baseline airway function (FEF(50), 600 vs. 676 ml/second, p < 0.04; FEF(25-75), 531 vs. 597 ml/second, p < 0.05). Infants exposed to tobacco smoking were approximately half as likely to develop a more than 30% decline in FEF(75) at any given methacholine dose (hazard ratio = 0.4, p = 0.001). In addition, a history of asthma in an extended family member increased the likelihood that an infant would develop a more than 30% decline in FEF(75) (hazard ratio = 1.7, p = 0.04). We conclude that exposure to parental smoking is associated with lower airway function but not increased airway reactivity; however, family history of asthma is associated with heightened airway reactivity.