Abstract Background: Antibody responses to Streptococcus gallolyticus subspecies gallolyticus (SGG) proteins, especially pilus protein Gallo2178, have been consistently associated with colorectal cancer risk. Previous case–control studies and prospective studies with up to 8 years of follow-up, however, were unable to decipher the temporality of antibody responses to SGG in the context of the long-term multistep development of colorectal cancer. In this study, we analyzed a large U.S. colorectal cancer cohort consortium with follow-up beyond 10 years for antibody responses to SGG. Methods: We applied multiplex serology to measure antibody responses to 9 SGG proteins in participants of 10 prospective U.S. cohorts (CLUE, CPSII, HPFS, MEC, NHS, NYUWHS, PHS, PLCO, SCCS, and WHI) including 4,063 incident colorectal cancer cases and 4,063 matched controls. Conditional logistic regression was used to assess whether antibody responses to SGG were associated with colorectal cancer risk, overall and by time between blood draw and diagnosis. Results: Colorectal cancer risk was increased among those with antibody responses to Gallo2178, albeit not statistically significant [OR, 1.23; 95% confidence interval (CI), 0.99–1.52]. This association was stronger for cases diagnosed <10 years after blood draw (OR, 1.40; 95% CI, 1.09–1.79), but was not found among cases diagnosed ≥10 years after blood draw (OR, 0.79; 95% CI, 0.50–1.24). Conclusions: In a large cohort consortium, we reproduced the association of antibody responses to SGG Gallo2178 with colorectal cancer risk for individuals diagnosed within 10 years after blood draw. Impact: This timing-specific finding suggests that antibody responses to SGG are associated with increased colorectal cancer risk only after tumorigenesis has begun. Cancer Epidemiol Biomarkers Prev; 27(10); 1186–94. ©2018 AACR.