Colorectal cancer is one of the most common malignancies. With continuous exploration of the interaction between tumor cells and the immune system, tumor immunotherapy has become a revolution. However, CRC remains one of the less effective tumors for immunotherapy. The tumor microenvironment plays an important role in tumorigenesis and progression. The aim of this study is to explore tumor microenvironment-related genes that can predict the prognosis of colorectal adenocarcinoma, and also to provide new ideas for the mechanism of tumor development as well as immunotherapy. After estimating Stromalscore and Immunescore of colorectal adenocarcinoma tumor samples according to RNA-Seq expression data downloaded from TCGA, we screened for TME-related differential genes. We filtered prognosis-related core genes by constructing protein-protein interaction networks and making one-factor cox analysis for prognosis. Finally, the relative content of 22 immune cells in tumor tissues was evaluated, and then immune cells associated with core genes were identified. We screened 773 differential genes related to the TME. Then we identified C3 as a core gene associated with prognosis. Single gene analysis showed that C3 expression was significantly higher in tumor tissues than in normal tissues (p < 0.001). High C3 expression was associated with lower overall survival (p = 0.046). Tumor immune cell analysis showed that mast cells resting, mast cells activated, T cells CD4 memory activated, eosinophils, and macrophages M0 were C3-associated immune cells. C3 has potential as a biomarker for colorectal adenocarcinoma and could provide new research ideas for the diagnosis and treatment of colorectal adenocarcinoma, especially for immunotherapy. © 2021. Federación de Sociedades Españolas de Oncología (FESEO).