Background: Chronic inflammation may play a role in colorectal cancer (CRC) pathogenesis. The relationship between soluble tumour necrosis factor receptor type II (sTNF-RII) and survival among CRC patients is not well defined. Methods: We prospectively evaluated the association between pre-diagnosis plasma levels of sTNF-RII and mortality in 544 CRC patients from the Nurses' Health Study and Health Professionals Follow-Up Study diagnosed from 1990 to 2010. Primary and secondary end points were overall and CRC-specific mortality, respectively. Cox proportional hazards models were used to calculate multivariate hazard ratios for mortality. Results: Higher sTNF-RII levels were significantly associated with increased overall mortality (multivariate HR=1.48, 95% CI 1.02–2.16, P-trend=0.006), but not with CRC-specific mortality (HR=1.23, 95% CI 0.72–2.08, P-trend=0.34). In subgroup analyses, among regular aspirin users, those with higher sTNF-RII levels had an adjusted HR of 0.52 (95% CI 0.20–1.33) for overall mortality compared with those with lower sTNF-RII levels, whereas among nonregular aspirin users the adjusted HR was 2.26 (95% CI 1.23–4.01, P for interaction=0.53). Conclusions: Among CRC patients, higher sTNF-RII levels are associated with a significant increase in overall mortality, but not CRC-specific mortality. The role of inflammation and anti-inflammatory medications in survival of CRC patients warrants further exploration