Objective <p>To evaluate the diagnostic accuracy of lung ultrasound score (LUS) for predicting response to surfactant replacement therapy (SRT) in preterm neonates with respiratory distress syndrome (RDS).</p> Methods <p>This prospective observational study conducted between August 2023 and July 2024 enrolled consecutive neonates ≤ 34&#xa0;weeks gestational age with RDS. All neonates underwent lung ultrasound following admission and prior to extubation. The LUS was compared against target condition/s (response to SRT, surfactant retreatment and extubation failure). Diagnostic accuracy measures including receiver operative characteristic (ROC) curves were estimated.</p> Result <p>Of 126 eligible neonates, 90 neonates were enrolled. The median (q1, q3) gestational age and birth weight of the neonates were 31.2 (29.4, 32.6) weeks and 1397 (1110, 1854) g, respectively. Surfactant was administered to 65 (72.2%) neonates, and 14 (15.6%) of these required additional doses. For predicting response to surfactant therapy (<i>n</i> = 65, at LUS threshold 12), AUC was 0.721 (95% CI 0.572–0.870), sensitivity 64.7% (95% CI 38.3–85.8%) and specificity 72.9% (95% CI 58.1–84.7%). For predicting extubation failure (<i>n</i> = 64, at LUS threshold 4), AUC was 0.785 (95% CI 0.645 − 0.924), sensitivity 71.4% (95% CI 56.7 − 83.4%) and specificity 80.0% (95% CI 51.9 − 95.7%).</p> Conclusion <p>LUS showed moderate sensitivity and specificity for predicting response to SRT and extubation failure in preterm neonates with RDS.</p> Trial Registry <p>Clinical Trial Registry-India; CTRI/2023/07/055318.</p>