BACKGROUND: Tumor development involves the critical role of programmed cell death (PCD), but the correlation between colon adenocarcinoma (COAD) and PCD-related genes is not clear. METHODS: Subtyping analysis of COAD was performed by consensus clustering based on The Cancer Genome Atlas (TCGA), with the AC-ICAM queue from the cBioportal database as a validation set. Immune infiltration of the samples was evaluated using CIBERSORT and Microenvironment Cell Populations (MCP)-counter algorithms. Patients' immunotherapy response was predicted by the TIDE and aneuploidy scores. Pathway enrichment analysis was conducted with gene set enrichment analysis (GSEA). A RiskScore model was established with independent prognostic PCD-related genes filtered by Cox regression analysis. The mafCompare function was used to compare the differences in mutation rates of somatic genes. Wound healing, transwell assays and Flow cytometer were applied to measure the cell migration, invasion and apoptosis. RESULTS: The patients were grouped into S1 and S2 subtypes based on a total of 21 PCD genes associated with the prognostic outcomes of COAD. Specifically, patients of S1 subtype were mainly related to the pathway activation in tumor invasion and deterioration and had a worse prognosis. A RiskScore model was established based on six prognostic genes, including two protective genes ( CONCLUSION: We constructed a RiskScore model with six PCD-related genes for the prognostic assessment of COAD, providing a valuable insight into the exploration of new targets for the prognostic improvement in COAD.