Objective: To determine whether minimal ventilation decreases death or bronchopulmonary dysplasia (BPD). Study design: Infants with birth weight 501 g to 1000 g and mechanically ventilated before 12 hours were randomly assigned to minimal ventilation (partial pressure of carbon dioxide [PCO2] target >52 mm Hg) or routine ventilation (PCO2 target <48 mm Hg) and a tapered dexamethasone course or saline placebo for 10 days, using a 2 × 2 factorial design. The primary outcome was death or BPD at 36 weeks' postmenstrual age. Results: After enrollment of 220 patients, the trial was halted because of unanticipated nonrespiratory adverse events related to dexamethasone therapy. The relative risk for death or BPD at 36 weeks in the minimal versus routine ventilation groups was 0.93 (95% CI, 0.77-1.12; P = .43). Ventilator support at 36 weeks was 1% in the minimal versus 16% in the routine group (P < .01). Major morbidities and long-term outcome were comparable in both treatment groups. Conclusions: With the sample size studied, minimal ventilation did not reduce the incidence of death or BPD. The reduced ventilator support at 36 weeks in the minimal ventilation group warrants further study of this intervention.