The effects of preterm birth and mechanical ventilation on growth of the alveolar region of the lung were assessed by morphometric and/or quantitative biochemical methods in the lungs from 104 perinatal and infant autopsies. The lungs of 4 preterm infants who died at 4-16 weeks age without having received mechanical ventilation were large relative to body weight but showed normal alveolar number and alveolar surface area. Infants treated by mechanical ventilation for hyaline membrane disease (HMD) and who died at ages from 1 week up to 14 months showed impairment in alveolar development evidenced by low alveolar number and a low alveolar surface area. Lung volume and total lung DNA values were relatively normal. Dilated alveolar ducts were a feature at all ages with emphysematous changes apparent in the longest surviving infants. Biochemical features included a high concentration of hydroxyproline, reflecting collagen, and a high desmosine concentration, reflecting elastin, in infants dying at less than 60 weeks postconceptional age. Changes in the lungs of infants ventilated at low pressures for conditions other than HMD were of a similar nature but less severe than those seen in the HMD group. These findings indicate that preterm birth alone may have little adverse influence on lung development but that conditions necessitating mechanical ventilation may lead to permanent impairment in alveolar development. We postulate that the standard technique of applying positive pressure ventilation may itself lead to impaired alveolar growth, although the effect is enhanced by concomitant HMD and BPD.