Lifestyle factors such as smoking and alcohol may influence colon cancer (CC) survival, but it is unclear whether their effects vary by tumour-infiltrating immune biomarkers. This study examined CC-specific survival by smoking and alcohol status, stratified by immune cell density, in a large population-based cohort. The study included 661 individuals who underwent surgery for stage II or III CC between 2004 and 2008 within two Health and Social Care (HSC) Trusts in Northern Ireland. Representative formalin-fixed, paraffin-embedded (FFPE) tumour blocks were retrieved, and immunohistochemistry (IHC) was performed on tissue microarrays constructed from both the central tumour and the invasive margin. Cox proportional hazards models were used to assess CC-specific survival, adjusting for key clinical and demographic confounders. Ever smoking, compared to never smoking, was associated with poorer CC-specific survival among individuals with lower densities of CD3+, CD4+ and FOXP3+ tumour-infiltrating immune cells. Among those with higher CD8+ cell density in the central tumour, ever smoking was linked to worse outcomes. Similar patterns were seen in the invasive margin, although these were not all statistically significant. No significant associations were observed between alcohol use and survival across any immune biomarker subgroups. Smoking was associated with poorer survival among patients with CC, and this association appears to be modified by the density of tumour-infiltrating immune cells.