Asthma-like symptoms and airway hyper-responsiveness (AHR) are frequently reported in children subsequent to premature birth and bronchopulmonary dysplasia (BPD). There is limited knowledge on the mechanisms underlying these respiratory manifestations. Generally, childhood asthma and AHR is described within a context of inheritance, allergy and eosinophilic airway inflammation, and often in relation to cigarette exposures. We investigated these factors in relation to current asthma and AHR in a population-based cohort of 81 young people, born with gestational age < or = 28 wk or birth weight < or = 1000 g, and in a matched term-born control population. In the pre-term population, asthma and AHR were additionally studied in relation to neonatal respiratory morbidity. At follow up, more pre-term than control subjects had asthma. Forced expiratory volume in first second (FEV1) was reduced, AHR was substantially increased, and the level of the urinary leukotriene metabolite E4 (U-LTE4) was increased in the pre-term population compared to the term-born. In control subjects, asthma and AHR was associated with a pattern consistent with inheritance, allergy, airway inflammation, and cigarette exposures. In the pre-terms, asthma and AHR was either unrelated or less related to these factors. Instead, AHR was strongly related to a neonatal history of BPD and prolonged requirement for oxygen treatment. In conclusion, asthma and AHR subsequent to extremely premature birth differed from typical childhood asthma with respect to important features, and AHR was best explained by neonatal variables. These respiratory manifestations thus seem to represent a separate clinical entity.