BACKGROUND: Premature birth poses significant health challenges, including respiratory distress syndrome (RDS). Corticosteroids reduce the incidence of RDS, but higher dexamethasone doses may lead to adverse neonatal outcomes, such as growth restriction and neurodevelopmental issues. Determining the appropriate dose is crucial to balance efficacy and safety. Dexamethasone is inexpensive and widely available in most low- and middle-income countries. This study aims to compare the efficacy and safety of 4-mg, 5-mg and 6-mg dexamethasone in preventing RDS among preterm infants. This trial aims to determine whether lower dexamethasone doses are as effective as the standard dose in preventing RDS in preterm infants. By assessing efficacy and potential adverse outcomes, this study will provide critical insights for optimizing treatment protocols and improving neonatal care. METHODS: This randomized controlled trial will include pregnant women with gestational ages between 29 RESULTS: The study requires 1,560 participants, accounting for a 15% loss to follow-up. The data will be analysed via descriptive statistics, chi-squared tests for categorical data, and one-way ANOVA or Kruskal-Wallis tests for continuous data. An independent Data Safety Monitoring Board will conduct interim analyses every 3 months to ensure participant safety and study integrity. DISCUSSION: This trial addresses the gap in research regarding optimal dexamethasone dosing for preventing RDS in preterm infants. The study will provide evidence on whether lower doses of dexamethasone (4 and 5 mg) are as effective as the standard 6-mg dose and will examine their potential adverse outcomes. The results will guide adjustments to medical practice guidelines, aiming to align them with clinical practices while ensuring safety and efficacy. Trial registration page https://www.thaiclinicaltrials.org/export/pdf/TCTR20220511003 10/05/2022.