Background <p>The pre-diagnosis plasma proteomic contexture of colon cancer patients may reflect host immune and biological conditions and potentially associate with survival outcomes. We aimed to characterize pre-diagnosis proteomic contextures in colon cancer patients and determine potential association with overall survival of the patients.</p> Methods <p>Baseline plasma samples collected at an average of 7.90&#xa0;years before diagnosis from colon cancer patients in the UK Biobank cohort were analyzed using Olink proteomics technology. Cox-regression analysis was applied to identify distinct pre-diagnosis proteomic contextures and determine their association with survival outcomes.</p> Results <p>In early-stage colon cancer, a 10-protein pre-diagnosis profile was identified, involving biological processes of extracellular matrix remodeling and immune evasion through deregulation of innate immune activation. Increased activity in these pathways before diagnosis was associated with poor survival outcomes. In late-stage cases, an 8-protein pre-diagnosis profile was linked to pathways involving in cell adhesion, angiogenesis, and pro-inflammatory response. Similarly, heightened activity in these pathways prior to diagnosis correlated with worse survival. When combined with two demographic factors age and sex, these proteomic profiles demonstrated strong predictive associations with survival outcomes at multiple time points post-diagnosis. The area under the receiver operating characteristic curve values were 0.85, 0.82, and 0.89 for early-stage cancer at 1, 5, and 10&#xa0;years, respectively, and 0.71, 0.72, and 0.79 for late-stage cancer over the same periods.</p> Conclusions <p>Biological processes like extracellular matrix remodeling and pro-inflammatory response are active well before diagnosis and may play a critical role in shaping colon cancer progression.</p>