Objective To evaluate the efficacy of noninvasive ventilation combined with vibrating mesh nebulization of pulmonary surfactant (PS) in preterm infants with respiratory distress syndrome (RDS) and to identify predictors of treatment failure. Methods Preterm infants with RDS (gestational age >28 weeks, birth weight >1 000 g) admitted to neonatal intensive care units at 12 hospitals between June 2023 and November 2024 were prospectively enrolled. All infants initially received nasal continuous positive airway pressure and were treated with PS administered via vibrating mesh nebulization. Infants were categorized into a success group or a failure group according to whether escalation to invasive mechanical ventilation via endotracheal intubation was required. Multivariable logistic regression was used to identify predictors of failure of vibrating mesh nebulized PS treatment. A prediction model was constructed, and its performance was assessed using receiver operating characteristic (ROC) curves and the area under the curve (AUC). Results A total of 126 preterm infants with RDS were included, with 107 (84.9%) in the success group and 19 (15.1%) in the failure group. Multivariable logistic regression analysis showed that nonstandard antenatal glucocorticoid use, a lower 1-minute Apgar score, chest radiograph showing RDS grade ≥III, and a lower ratio of partial pressure of arterial oxygen (PaO₂) to fraction of inspired oxygen (FiO₂) (PaO₂/FiO₂) at 30 minutes after treatment were independent predictors of treatment failure (P<0.05). The prediction model for treatment failure based on these four factors yielded an AUC of 0.857 (95%CI: 0.789-0.943), with a sensitivity of 84.21% and a specificity of 74.53%. The cutoff values for the 1-minute Apgar score and PaO₂/FiO₂ at 30 minutes after treatment were <8 and <220 mmHg, respectively. Conclusions Noninvasive ventilation combined with vibrating mesh nebulization of PS achieves a high success rate in preterm infants with RDS who had a gestational age >28 weeks and a birth weight >1 000 g. Nonstandard antenatal glucocorticoid use, a 1-minute Apgar score <8, chest radiograph showing RDS grade ≥III, and PaO₂/FiO₂ <220 mmHg at 30 minutes after treatment are independent predictors of treatment failure.