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Background: The issue of retreatment with surfactant of infants with respiratory distress syndrome (RDS) has been poorly investigated. Our aim was to identify possible clinical predictors of the need for multiple doses of surfactant in a large cohort of very preterm infants., Methods: Data were analyzed from three previous studies on infants born between 25 + 0 and 31 + 6 weeks of gestation with RDS who were treated with surfactant., Results: We studied 448 infants. Among them 306 (68%) were treated with a single dose of surfactant and 142 (32%) were treated with multiple doses. Multivariable mixed effects logistic regression analysis showed that the odd of requiring multiple doses of surfactant was significantly lower in patients with higher gestational age (27-28 vs. 25-26 wks: OR 0.46, 95% C.l. 0.26-0.79; ≥29 vs. 25-26 wks: OR 0.34, 95% C.l. 0.13-0.85; overall P = 0.013), while it increased in infants born to mothers with hypertensive disorders of pregnancy (OR 2.53, 95% C.l. 1.49-4.31; P < 0.001) and with hemodynamically significant PDA (OR 2.74, 95% C.l. 1.66-4.53, P < 0.001)., Conclusions: Gestational age, hypertension in pregnancy, and hemodynamically significant PDA can predict the need for multiple doses of surfactant. Further investigation is needed to evaluate if these sub-groups of preterm infants represent specific phenotypes of RDS who deserve a peculiar surfactant treatment., Competing Interests: Declarations. Ethics approval and consent to participate: All studies used for pooled analyses were approved by pediatric ethics committees of Tuscany (ID 29/2011, ID 234/2019, and ID 58/2019, respectively) and carried out in accordance with the 1964 Declaration of Helsinki. Infants were enrolled after informed parental consent. Only data of infants who were treated with surfactant were analyzed. Local ethics committees approved the study. Parental consent was not required because this is a retrospective study and data were anonymized. Consent for publication: Not applicable. Competing interests: Prof. Carlo Dani received honoraria from Chiesi Farmaceutici SpA and Vyaire Medical Inc. for scientific consultancies. Other authors declare that there are no conflicts of interests. Prof. Carlo Dani and Dr. Raffaele Falsaperla are members of the Editorial Board of the Italian Journal of Pediatrics., (© 2024. The Author(s).)