Ventilated preterm infants prone to the development of bronchopulmonary dysplasia have been shown to have increased inflammatory mediators in their tracheal aspirates. High frequency oscillatory ventilation (HFOV) is thought to be less traumatic than intermittent positive pressure ventilation (IPPV) in premature infants with surfactant deficiency, and therefore may reduce the inflammatory response in tracheobronchial aspirates. We randomized 76 premature infants requiring mechanical ventilation (birth weight 420-1830 g, median 840 g, gestational age 23 3/7 to 29 2/7 wk, median 26 4/7 to receive either an IPPV with a high rate (60-80/min) and low peak pressures, or an HFOV aiming at an optimization of lung volume, within 1 h of intubation. Tracheal aspirates were systematically collected during the first 10 d of life and analyzed for albumin, IL-8, leukotriene B4 (LTB4), and the secretory component (SC) for IgA as a reference protein. Bacterially colonized samples were excluded. On the treatment d 1, 3, 5, 7, and 10, the resulting median values of albumin (milligrams/mg of SC) were 28, 23, 24, 18, and 10, in IPPV-ventilated infants, and 33, 28, 18, 25, and 39 in HFOV-ventilated infants, respectively. Median IL-8 values (nanograms/mg of SC) were 671, 736, 705, 1362, and 1879 (IPPV) and 874, 1713, 1029, 1426, and 1823 (HFOV), respectively, and median LTB4 values (nanograms/mg of SC) were 26, 13, 27, 22, and 11 (IPPV) and 15, 12, 7, 12, and 16 (HFOV), respectively. Values were similar in IPPV- and HFOV-ventilated infants, and no significant differences were noted. We conclude that HFOV, when compared with a high rate low pressure IPPV, does not reduce concentrations of albumin, IL-8, and LTB4 in tracheal aspirates of preterm infants requiring mechanical ventilation.