Bronchial responsiveness is closely associated with asthma in schoolchildren. We wished to test the hypothesis that bronchial responsiveness in the neonatal period might be a risk factor for lower-respiratory illnesses (LRI), typically cough and wheezing with viral infection, in infants. A cohort of 73 full-term healthy infants of atopic parents were observed during the first year of life. Respiratory illness was recorded and ascertained retrospectively by questionnaires administered to parents at 6-mo intervals, and infants were classified as having: LRI (one or more episode of wheezing in the first year) or no LRI (no wheezing). At approximately 1 mo of age, lung function was measured under sedation, and bronchial responsiveness (BR) to histamine aerosol was determined and expressed as PC30, the provocative concentration of histamine that induced a 30% decrease in maximum flow at FRC (V'maxFRC) by the squeeze technique. For the whole group, no index of lung function predicted subsequent wheezing. Among boys, however, there was a trend toward a lower V'maxFRC in those who subsequently developed LRI than in the group without LRI (median values 62 versus 98 ml/s; 95% CI: -1 to 68; p = 0.06), while among girls the major difference was in PC30, for which those who subsequently had LRI were significantly more responsive as neonates (PC30 was lower) than the group without LRI (1.4 versus 8.3 g/L; 95% CI: 1.0 to 13.1; p < 0.05). These findings suggest that sex differences in airway structure and responsiveness present soon after birth, and representing differences in fetal lung development, are associated with differences in the risk of subsequent LRI with wheezing.(ABSTRACT TRUNCATED AT 250 WORDS)