Recurrent pregnancy loss (RPL) is affecting 3-5% of the women who are expecting to have babies annually. However, the molecular changes of RPL patients have not been well characterized before. In the current study, we aimed to discover the differentially expressed genes (DEGs) in decidua from RPL patients by utilizing RNA sequencing (RNA-seq) technology. Four RPL patients and three control women were recruited to conduct RNA-seq, and 153 genes comprising 69 were upregulated and 84 downregulated showed different expression levels between the health control and RPL groups. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to identify potential biological processes associated with RPL. We recognized that type I interferon signaling pathway and TNF signaling pathway are significantly upregulated in women with RPL. Upregulated expression of MX1, IFI27, and ISG15 in type I interferon signaling pathway and TNFRSF21 in TNF signaling pathway were validated by an extended sample of 15 RPL patients and 12 control women, by quantitative real-time polymerase chain reaction (qRT-PCR). In conclusion, the results of the current study revealed molecular changes in decidua which may reflect the intrauterine circumstance when pregnancy loss happens and potentially contributes to RPL.