We conducted a prospective, randomized, double-blind trial to assess the efficacy and safety of pulse doses of dexamethasone on survival without supplemental oxygen in very low birth weight infants at high risk of having chronic lung disease. Seventy-eight infants with birth weights < or = 1500 gm who were ventilator dependent at 7 days of postnatal age were randomly assigned to receive pulse doses of dexamethasone, 0.5 mg/kg per day, divided twice daily (n = 39), or an equivalent volume of saline solution placebo (n = 39), for 3 days at 10-day intervals until they no longer required supplemental oxygen or assisted ventilation, or reached 36 weeks of postmenstrual age. At study entry, the groups did not differ by birth weight, gestational age, or severity of lung disease. At 36 weeks of postmenstrual age, there was both a significant increase in survival rates without oxygen supplementation (p = 0.03) and a significant decrease in the incidence of chronic lung disease (p = 0.047) in the group that received pulse therapy. Supplemental oxygen requirements were less throughout the study period in the group that received repeated pulse doses of dexamethasone (p = 0.013). The total numbers of deaths and the durations of supplemental oxygen, ventilator support, and hospital stay did not differ between groups. Recorded side effects in the pulse therapy group were minimal and included an increase in the use of insulin therapy for hyperglycemia (p < 0.05). We conclude that in this population of very low birth weight infants, treatment with pulse doses of dexamethasone resulted in improvement in pulmonary outcome without clinically significant side effects.