Colorectal cancer is the third most diagnosed malignancy worldwide and survival outcomes remain poor. Research is focused on the identification of novel prognostic and predictive biomarkers to improve clinical practice. There is robust evidence in the literature that inflammatory cytokine interleukin-6 (IL6) is elevated systemically in CRC patients and that this phenomenon is a predictor of poor survival outcome. However, evidence is more limited for the role of IL6 and its cognate receptor, IL6R, within the tumour epithelium and microenvironment. This study aimed to investigate IL6 and IL6R expression in a large cohort of retrospectively collected patient tumour specimens and determine association with clinical outcomes and characteristics. High expression of IL6R in the tumour epithelium was associated with reduced cancer-specific survival in patients with right-sided colon cancer. In these patients, high IL6R expression was also associated with an increased systemic neutrophil-to-lymphocyte ratio. A high number of copies of IL6 mRNA within the tumour-associated stroma, but not epithelium, was associated with reduced cancer-specific survival. The results from this study have validated IL6R as a marker of poor prognosis in a subgroup of CRC patients and identified the spatially resolved prognostic nature of intra-tumoural IL6 expression. This study has also highlighted the need for investigation of IL6/IL6R-targeted therapies as novel treatment strategies for patients with colon cancer.