Background: Respiratory distress syndrome (RDS) is one of the most common causes of neonatal respiratory failure and neonatal death, however, its clinical characteristics are very different from premature RDS, and these characteristics have not been well documented as yet. This study was to investigate the pathogenesis, clinical characteristics and management strategies of RDS in full-term neonates, with the aim of developing a working protocol for improving the outcome in full-term neonates with RDS. Methods: A total of 125 full-term infants with RDS were enrolled in this study. Their clinical and laboratory data were collected for analyzing the characteristics of full-term neonatal RDS. Results: (1) The 125 cases included 94 male and 31 female infants, vaginal delivery occurred in 80 cases and cesarean section in 45 cases. (2) The onset time of RDS was (3.11±3.59) hours after birth. (3)The possible reasons included severe perinatal infections in 63 patients, elective cesarean section in 34 cases, severe birth asphyxia in 12 patients, meconium aspiration syndrome in 9 patients, pulmonary hemorrhage in 4 patients and maternal diabetes in 3 patients. (4) Complications included multiple organ system failure (MOSF) in 49 patients, persistent pulmonary hypertension of newborn (PPHN) in 25 patients, acute renal failure in 18 patients, severe hyperkalemia in 25 patients, severe metabolic acidosis in 6 cases, severe myocardial injury in 9 cases, pulmonary hemorrhage in 3 cases, disseminated intravascular coagulation in 14 patients and shock in 12 patients.(5) Four patients died, the mortality was therefore 3.2% with the main cause of septicemia complicating of MOSF, but their prognosis was improved while comprehensive treatment measures including early mechanical ventilation and broad spectrum antibiotics were taken into account. Conclusions: RDS is not an uncommon disease in full-term infants and is associated with a higher mortality, its clinical characteristics are very different from premature RDS, and its onset is earlier and is more likely to develop into PPHN and/or MOSF. The main cause of death is severe infection complicating of MOSF and most patients require prolonged mechanical ventilation. Comprehensive management strategies will help to improve patient's prognosis.