BACKGROUND: Although there is evidence that Fusobacterium spp. in colon tissue is associated with prognosis, less is known about the association between antibody response to antigens expressed by fusobacteria and colorectal cancer-specific mortality. METHODS: Antibody responses to 11 Fusobacterium nucleatum (ATCC 25586) antigens were measured in prediagnostic blood for 471 incident colorectal cancer cases (median time to diagnosis = 3.4 years), among whom 188 colorectal cancer-specific deaths and 250 total deaths were confirmed over a median follow-up of 9.2 years in the European Prospective Investigation into Cancer and Nutrition cohort. Cox models were conducted to examine associations between antigen seropositivity and colorectal cancer-specific mortality. RESULTS: Seropositivity to fusobacterial antigens was not associated with overall or colorectal cancer-specific mortality, individually or combined. Similar results were observed when restricting to patients who donated blood <3 years prior to cancer diagnosis. When restricting to individuals diagnosed at an earlier age of onset (<55 years; N = 74), we observed positive associations for seropositivity to three fusobacteria antigens reflecting different putative autotransporter adhesins. The strongest association was for Fn1893 antigen seropositivity (HR, 6.95; 95% confidence interval, 1.78-27.2, compared with none) and colorectal cancer-specific mortality, but confidence intervals were wide. CONCLUSIONS: Although null overall, this is the first study to observe an association between antibody response to fusobacteria and colorectal cancer-specific mortality among individuals with earlier-onset colorectal cancer. Future studies are needed to confirm these findings and understand the role of systemic antibody responses to fusobacteria in cancer. IMPACT: Specific antigens expressed by fusobacteria may play a role in mortality from earlier-onset colorectal cancers.