OBJECTIVE To explore the association between total serum bilirubin (TSB) level in umbilical cord blood (UCB) and the occurrence and/or severity of respiratory distress syndrome (RDS) in very low birth weight (VLBW) infants. METHODS We performed a prospective study of 579 VLBW infants. The mean TSB level in UCB (1.8 mg/dL) was used to divide the cohort into two groups: neonates with levels <1.8 mg/dL and those with levels >1.8 mg/dL. Demographic and clinical characteristics of the 2 groups, including diagnosis of RDS, need for ventilation, peak fraction of inspired oxygen (FiO2), oxygenation index (OI), and duration of respiratory support, were compared. RESULTS Three hundred and twenty-four infants were included in the low-TSB group and 255 infants were included in the high-TSB group. RDS was less frequent in the high TSB group than in the low one (46.3% vs. 56.6%, P=0.01). A negative association between TSB level in UCB and the occurrence of RDS [odds ratio (OR)=0.620; 95% confidence interval (CI) 0.440-0.873, P=0.006] was observed. However, lower TSB in UCB was not associated with the maximum FiO2, OI, or duration of mechanical ventilation. CONCLUSIONS VLBW infants with low TSB levels in UCB were more likely to develop RDS. However, in conjunction with surfactant replacement therapy, no correlation was found between TSB levels in UCB and the severity of RDS. The negative association between high TSB in UCB and RDS warrants further investigation.