Aim To explore the key genes in the blood transcriptome of atherosclerosis patients based on blood transcriptomics. Methods Three datasets GSE12288, GSE27034 and GSE90074 were extracted from the GEO database and performed the merging and normalization processing. The differential genes in peripheral blood samples of atherosclerosis patients and controls were analyzed, and enrichment analysis of differentially expressed genes were performed. Then weighted gene co-expression network analysis was performed for all genes. Using differentially expressed genes to construct protein-protein interaction (PPI) network, and using CytoHubba to screen key genes based on co-expression network and PPI network. And the expression levels of key genes were detected by RT-qPCR. Results 74 down-regulated genes and 145 up-regulated genes were identified between atherosclerosis patients and controls. GO and KEGG enrichment analyses revealed that they were significantly enriched in neutrophil activation, granulocyte activation, cytokine-cytokine receptor interaction and chemokine signaling pathway. In addition, the top 10 genes in the co-expression network and the top 20 genes in the PPI network were also identified, in which PRF1, NKG7, GZMB and CCL5 played a high core role in the PPI network and co-expression network. The RT-qPCR results showed that compared with the non coronary atherosclerosis controls, the mRNA expression levels of PRF1 and GZMB in peripheral venous blood peripheral blood mononuclear cell (PBMC) of coronary atherosclerosis patients were significantly reduced (P＜0.05), while the mRNA expression levels of NKG7 and CCL5 were significantly increased (P＜0.05). Conclusion PRF1, GZMB, NKG7 and CCL5 may be key genes in the blood transcriptome of atherosclerosis patients, and are expected to be potential biomarkers for diagnosis and treatment of atherosclerosis.