Preterm birth (PTB) is the leading cause of newborn deaths around the world. Spontaneous preterm birth (sPTB) accounts for two-thirds of all preterm births; however, there remains an unmet need of detecting and preventing sPTB. Although the dysregulation of the immune system has been implicated in various studies, small sizes and irreproducibility of results have limited identification of its role. Here, we present a cross-study meta-analysis to evaluate genome-wide differential gene expression signals in sPTB. Acomprehensive search of the NIH genomic database for studies related to sPTB with maternal whole blood samples resulted in data from three separate studies consisting of over 300 samples. After aggregating and normalizing these gene datasets and performing a meta-analysis, we identified 210 genes that were differentially expressed in PTB relative to term birth. These genes were enriched in immune related pathways, showing upregulation of innate immunity and downregulation of adaptive immunity in women who delivered preterm. Interestingly, an additional analysis found several of these differentially expressed at mid-gestation, suggesting their potential to be a clinically relevant biomarker. Furthermore, a tissue-specific analysis identified 473 genes differentially expressed in preterm cord blood samples. However, these genes demonstrated downregulation of the innate immune system, a stark contrast to findings using maternal blood samples. These immune related findings were further confirmed by cell deconvolution as well as upstream transcription and cytokine regulation analyses. Overall, this study identified a strong immune signature related to PTB as well as several potential biomarkers that could be translated to clinical use.