OBJECTIVES: In order to evaluate the impact of the surfactant of choice selection, primary end points were to compare the average number of doses per patient, need for mechanical ventilation on day 3, hospital length of stay, and in-hospital mortality between calfactant and poractant alfa in preterm infants with respiratory distress syndrome (RDS). Secondary outcomes included administration complications, development of bronchopulmonary dysplasia (BPD), and estimated average per patient cost among the study population. METHODS: A retrospective chart review was performed at a level IV neonatal intensive care unit between January 2020 and December 2021 to compare the efficacy, safety, and pharmacoeconomic outcomes -following a surfactant of choice switch from calfactant to poractant alfa in preterm infants with RDS. RESULTS: Final analysis included 253 premature infants with gestational age (GA) between 22 and 36 weeks who met inclusion criteria. A total of 118 patients who received calfactant required higher average number of doses, 1.5 vs 1.3 doses (p = 0.031), and had more administration complications than 135 patients who received poractant alfa (10.2 vs 2.2%, p = 0.008). The need for redosing, mechanical ventilation on day 3, hospital length of stay, in-hospital mortality, and development of BPD were comparable between both groups. However, the estimated average per patient cost for poractant alfa was 32% higher than calfactant ($1,901 vs $1,439, p <0.001). CONCLUSIONS: Despite the pharmacoeconomic disadvantage, preterm infants who received poractant alfa needed fewer doses and were less likely to have administration complications compared with those who received calfactant.