Objective: The purpose of this article is to describe how a neonatal intensive care unit (NICU) was able to reduce substantially the use of postnatal dexamethasone in infants born between 501 and 1250 g while at the same time implementing a group of potentially better practices (PBPs) in an attempt to decrease the incidence and severity of chronic lung disease (CLD)., Methods: This study was both a retrospective chart review and an ongoing multicenter evidence-based investigation associated with the Vermont Oxford Network Neonatal Intensive Care Quality Improvement Collaborative (NIC/Q 2000). The NICU specifically made the reduction of CLD and dexamethasone use a priority and thus formulated a list of PBPs that could improve clinical outcomes across 3 time periods: era 1, standard NICU care that antedated the quality improvement project; era 2, gradual implementation of the PBPs; and era 3, full implementation of the PBPs. All infants who had a birth weight between 501 and 1250 g and were admitted to the NICU during the 3 study eras were included (era 1, n = 134; era 2, n = 73; era 3, n = 83). As part of the NIC/Q 2000 process, the NICU implemented 3 primary PBPs to improve clinical outcomes related to pulmonary disease: 1) gentle, low tidal volume resuscitation and ventilation, permissive hypercarbia, increased use of nasal continuous positive airway pressure; 2) decreased use of postnatal dexamethasone; and 3) vitamin A administration. The total dexamethasone use, the incidence of CLD, and the mortality rate were the primary outcomes of interest. Secondary outcomes included the severity of CLD, total ventilator and nasal continuous positive airway pressure days, grades 3 and 4 intracranial hemorrhage, periventricular leukomalacia, stages 3 and 4 retinopathy of prematurity, necrotizing enterocolitis, pneumothorax, length of stay, late-onset sepsis, and pneumonia., Results: The percentage of infants who received dexamethasone during their NICU admission decreased from 49% in era 1 to 22% in era 3. Of those who received dexamethasone, the median number of days of exposure dropped from 23.0 in era 1 to 6.5 in era 3. The median total NICU exposure to dexamethasone in infants who received at least 1 dose declined from 3.5 mg/kg in era 1 to 0.9 mg/kg in era 3. The overall amount of dexamethasone administered per total patient population decreased 85% from era 1 to era 3. CLD was seen in 22% of infants in era 1 and 28% in era 3, a nonsignificant increase. The severity of CLD did not significantly change across the 3 eras, neither did the mortality rate. We observed a significant reduction in the use of mechanical ventilation as well as a decline in the incidence of late-onset sepsis and pneumonia, with no other significant change in morbidities or length of stay., Conclusions: Postnatal dexamethasone use in premature infants born between 501 and 1250 g can be sharply curtailed without a significant worsening in a broad range of clinical outcomes. Although a modest, nonsignificant trend was observed toward a greater number of infants needing supplemental oxygen at 36 weeks' postmenstrual age, the severity of CLD did not increase, the mortality rate did not rise, length of stay did not increase, and other benefits such as decreased use of mechanical ventilation and fewer episodes of nosocomial infection were documented.