Rationale: Bronchopulmonary dysplasia (BPD) is a frequent morbidity of preterm infants characterized by prolonged need for ventilatory support in an intensive care environment. BPD is characterized by persistently thick, cellular distal airspace walls. In normally developing lungs, by comparison, remodeling of the immature parenchymal architecture is characterized by thinning of the future alveolar walls, a process predicated on cell loss through apoptosis. Objective: We hypothesized that minimizing lung injury, using high-frequency nasal ventilation to provide positive distending pressure with minimal assisted tidal volume displacement, would increase apoptosis and decrease proliferation among mesenchymal cells in the distal airspace walls compared to a conventional mode of support (intermittent mandatory ventilation). Methods: Accordingly, we compared two groups of preterm lambs: one group managed by high-frequency nasal ventilation to a second group managed by intermittent mandatory ventilation. Each group was maintained for 3 days. Measurements and Main Results: Oxygenation and ventilation targets were sustained with lower airway pressures and less supplemental oxygen in the high-frequency nasal ventilation group, in which alveolarization progressed. Thinning of the distal airspace walls was accompanied by more apoptosis, and less proliferation, among mesenchymal cells of the high-frequency nasal ventilation group, based on morphometric, protein abundance, and mRNA expression indices of apoptosis and proliferation. Conclusion: Our study shows that high-frequency nasal ventilation preserves the balance between mesenchymal cell apoptosis and proliferation in the distal airspace walls, such that alveolarization progresses.