<p>Down syndrome (DS), a typical chromosomal disease caused by all or part of an extra genomic copy of chromosome 21. Few reports have investigated roles of competing endogenous RNA (ceRNA)-mediated regulatory mechanisms in DS pathogenesis. RNA from PBMCs of cord blood from DS and non-DS fetuses was used for RNA-Seq to profile lncRNAs, miRNAs, and mRNAs. Bioinformatics revealed DS-associated differential gene expression. Predicted miRNA-mRNA/lncRNA interactions were used to build and visualize ceRNA networks in Cytoscape. A total of 216 DEmiRNAs, 651 DElncRNA and 15,789 DEmRNA transcripts were identified in umbilical cord blood PBMC RNA preparations from DS and non-DS control subjects. KEGG pathway enrichment analysis showed that DEmRNAs were involved in pathways such as Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, etc., which are closely related to DS. The 11 mRNAs corresponding to the highest degree PPI network nodes (RPS27A, UBA52, UBC, RPL11, RPS27, MRPS7, RPL23, RPL9, NFKB1, RBX1, and RELA) may play important roles in expression of DS-associated phenotypic characteristics. Finally, we constructed upregulated and downregulated lncRNA-miRNA-mRNA ceRNA sub-networks and found several pairs of ceRNAs that might be involved in DS. MIAT might serve as a ceRNA to sponge hsa-miR-378c and ultimately regulate the expression of RBX1 to affect the cell cycle and lead to DS occurrence. In this study, we comprehensively analysed gene regulatory mechanisms associated with DS progression. The lncRNA-associated ceRNAs identified here may contribute to DS diagnosis and treatment.</p>