Recurrent illness involving wheezing during the first years of life is transient in most children. The role of bronchial hyperresponsiveness as a factor influencing the persistence of wheezing from infancy to school age remains unknown. In a prospective study we investigated whether infants who wheezed and subsequently developed persistent asthma differed from infants who wheezed and later became asymptomatic either in the initial degree of bronchial hyperresponsiveness or in the persistence of bronchial hyperresponsiveness with age. One hundred and twenty-nine infants with three or more wheezing episodes before 2 yr of age were followed during 4 yr with a clinical evaluation and a methacholine challenge performed every 6 mo until the child was 4 yr old and once per year thereafter. The clinical score significantly improved with time in most children. The proportion of children with persistent wheezing after 2 and 4 yr of follow-up was only 31% and 20%, respectively. Persistent wheezers had significantly lower VmaxFRC values at initial evaluation and higher SRaw values at the end of follow-up than infants who became asymptomatic. We used transcutaneous oxygen tension (PtcO(2)) to measure the response to methacholine. No significant difference in PD(15) PtcO(2) between groups with subsequently different clinical progression was observed at initial evaluation. Bronchial hyperresponsiveness persisted 4 yr later in all children but children with persistent wheezing showed significantly lower PD(15) PtcO(2) values than children who became asymptomatic, as early as 30 mo of age. However, an acceptable early PD(15) PtcO(2) cut-off point predictive for subsequent clinical progression could not be identified. The level of bronchial hyperresponsiveness in infants who wheezed was not predictive of the persistence of asthma 4 yr later.