Abstract: Objective To identify orthologous lncRNAs in human and mice and the species specificity of their epigenetic regulatory functions. Methods The human/mouse whole-genome pairwise alignment (hg19/mm10, genome.UCSC.edu) was used to identify the orthologues in 13 562 and 10 481 GENCODE-annotated human and mouse lncRNAs. The Infernal program was used to search the orthologous sequences of all the exons of the 13562 human lncRNAs in mouse genome (mm10) to identify the highly conserved orthologues in mice. LongTarget program was used to predict the DNA binding sites of the orthologous lncRNAs in their local genomic regions. Gene Ontology analysis was carried out to examine the functions of genes. Results Only 158 orthologous lncRNAs were identified in humans and mice, and many of these orthologues had species- specific DNA binding sites and epigenetic target genes. Some of the epigenetic target genes executed important functions in determining human and mouse phenotypes. Conclusions Only a few human and mouse lncRNAs are orthologues, and most of lncRNAs are species-specific. The orthologous lncRNAs have species-specific epigenetic target genes, and species-specific epigenetic regulation greatly contributes to the differences between humans and mice.