Aim To investigate the potential mechanisms and immunological correlation of below-the-knee atherosclerosis obliteran (BTK). Methods The GSE100927 dataset was downloaded from the Gene Expression Omnibus.Differentially expressed genes of BTK were screened by using “limma” package of the R and weighted correlation network analysis (WGCNA). Signaling pathway enrichment analysis was performed by “clusterProfiler” package of the R. The protein-protein interaction network was constructed, and the core genes associated with BTK were screened. The differences of the core genes’ expression between the BTK samples and normal samples were analyzed, and the area under the receiver operating characteristic curve was used to evaluate the diagnostic efficacy of the core genes. The CIBERSORT was used to evaluate the distribution of immune cells in each sample and to calculate the differences between the BTK samples and normal samples. Results 153 genes were up-regulated and 63 genes were down-regulated in BTK. WGCNA results indicated that the differential expression genes in BTK were mainly up-regulated, involving signaling pathways such as cholesterol metabolism and platelet activation; protein tyrosine phosphatase receptor type C (PTPRC), Spi-1 proto-oncogene (SPI1),colony stimulating factor 1 receptor (CSF1R), and Fc gamma receptor Ⅲa (FCGR3A) were probably the core genes in BTK, which have good diagnostic efficacy. BTK was positively correlated with the degree of infiltration of monocytes (r＝0.419, P＝0.037) and negatively correlated with the degree of infiltration of M2 macrophages (r＝－0.491, P＝0.013). Conclusion The BTK involved various signaling pathways such as cholesterol metabolism and platelet activation and was closely related to monocyte- and macrophage-mediated immune responses. PTPRC, SPI1, CSF1R, and FCGR3A may be the core genes of BTK.