PURPOSE: Recent studies have addressed the association between lung development and long-noncoding RNAs (lncRNAs). But few studies have investigated the role of lncRNAs in neonatal respiratory distress syndrome (RDS). Thus, this study aimed to compare the expression profile of circulating lncRNAs between RDS infants and controls. METHODS: 10 RDS infants and 5 controls were enrolled. RDS patients were further divided into mild and severe RDS subgroups. Blood samples were collected for the lncRNA expression profile. Subsequently, differentially expressed lncRNAs were screened out. Bioinformatics analysis was applied to establish a co-expression network of differential lncRNAs and mRNAs, and predict the underlying biological functions. RESULTS: A total of 135 differentially expressed lncRNAs were identified, including 108 upregulated and 27 downregulated lncRNAs (fold-change>2 and <0.05) among the three groups (non-RDS, mild RDS and severe RDS groups). Of these lncRNAs, four were selected as showing higher fold changes and validated by qRT-PCR. ENST00000470527.1, ENST00000504497.1, ENST00000417781.5, and ENST00000440408.5 were increased not only in the plasma of total RDS patients but also in the severe RDS subgroup. Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses showed that differentially expressed lncRNAs may play important roles in RDS through regulating PI3KAkt, RAS, MAPK, and TGF-β signaling pathways. CONCLUSION: The present results found that ENST00000470527.1, ENST00000504497.1, ENST00000417781.5, and ENST00000440408.5 may be invol ved in RDS. This could provide new insight into research of the potential pathophysiological mechanisms of preterm RDS.