Colorectal cancer had a low incidence several decades ago. However, it has become predominant cancer and now accounts for approximately 10% of cancer-related mortality in western countries. The 'rise' of colorectal cancer in developed countries can be attributed to the increasingly ageing population, unfavourable modern dietary habits and an increase in risk factors such as smoking, low physical exercise and obesity. The current study aimed to Develop a robust prognostic immune-related gene pair [IRGP] model to estimate the overall survival of patients With COAD. The gene expression profiles and clinical information of patients with colon adenocarcinoma were obtained from the TCGA and GEO databases and were divided into training and validation cohorts. Immune genes were selected that showed a significant association with prognosis. Thus, we aim to build a robust immune-related gene pairs [IRGPs] signature that can estimate prognosis for CRC. Gene expression profiles and clinical information of CRC patients were collected from six public cohorts, divided into training cohort [n = 275] and five independent validation cohorts [n = 275]. Within 124 immune genes, a 17 IRGPs signature consisting of 28 unique genes was constructed which was significantly associated with the survival. In the validation cohorts, the IRGPs signature significantly stratified patients into high- vs low-risk groups in terms of prognosis across and within subpopulations with early stages disease. It was prognostic in univariate and multivariate analyses. Several biological processes, including response to the bacterium, were enriched among genes in the IRGPs signature. Macrophage M2 and mast cells were significantly higher in the high-risk risk group compared with the low-risk group. The IRGPs signature achieved higher accuracy than commercialized multigene signatures for estimation of survival