Background: In the early newborn period, hyaline membrane disease (HMD) or respiratory distress syndrome (RDS) is a leading cause of morbidity and mortality. It occurs in 7% - 50% of neonates. Our objective was to determine serum endocan role in the diagnosis and the prognosis of RDS in neonates. Methods: This prospective controlled study was carried out on 80 preterm neonates ≤ 34 weeks gestation at Neonatal Intensive Care Unit. They were diagnosed with RDS, and were classified into two groups: Group I consisted of 40 preterm newborns diagnosed with RDS, two blood samples were withdrawn. 1^st at birth (1^st day) and 2^nd after 4 days. Group II consisted of 40 healthy preterm neonates, blood samples were withdrawn at day1. Results: There was a significant high serum endocan level in dead cases in comparison with survived cases (P=0.001). Serum endocan level in RDS group showed an area under the curve of 0.867, which gave very good performance (p value was 0.001) at a cut of value > 450 ng/ml. Serum endocan level had a sensitivity of 88% (was able to identify 88% of cases that had RDS) and a specificity of 83% (identified 83% of cases that did not have RDS), with positive predictive value of 83%, negative predictive value of 87%, and accuracy 85%. Conclusions: Levels of serum endocan are significantly elevated in preterm neonates with RDS. Serum endocan level had positive correlation with severity of RDS. Serum endocan levels decreased after 3 days in preterm neonates with RDS.