Objective:To search for the key genes influencing the resistance of rectal cancer to chemoradiotherapy based on the weighted gene co-expression network analysis (WGCNA).Methods:The data were collected from gene expression omnibus. The whole genome expression data GSE119409 of patients receiving radiotherapy and chemotherapy were obtained by gene expression ominibus. The weighted gene co-expression networks of pathological complete response group and non-pathological complete response group were constructed respectively. NetRep conservative evaluation method was used to comprehensively analyze the three key network attributes of gene connectivity, gene significance and module membership of each node in the network module, and to determine the key genes closely related to the sensitivity of rectal cancer to radiotherapy and chemotherapy.Results:Network modules including black, blue, green, yellow and purple were obtained by WGCNA, and five key genes including SLC22A14, SIDT2, CABP4, EPHB6 and RAB11B were screened out.Conclusions:Five gene co-expression network modules and five key genes related to chemoradiotherapy resistance of rectal cancer were screened by weighted gene co-expression network analysis, which provided clues for finding molecular markers and potential therapeutic targets for neoadjuvant chemoradiotherapy resistance evaluation.