Abstract Auto-antibodies to tumor suppressor p53 are found in a subset of colorectal cancer (CRC) patients. A prospective cohort study in the US (Cancer Prevention Study II) has recently reported a statistically significant 1.8-fold increased odds for the development of CRC based on pre-diagnostic sero-positivity for p53; the magnitude of this association decreased with longer time-span between blood sampling and diagnosis. In the present study, we sought to examine this association in a large US CRC cohort consortium to evaluate the potential utility of p53 auto-antibodies as an early CRC detection biomarker. Methods: Antibody responses to p53 were measured in pre-diagnostic blood samples of 3,702 incident CRC cases (median [range] follow-up: 7.3 years [0–40 years]) and an equal number of controls, matched by age, race, and sex, from 9 US prospective cohorts. The association of sero-positivity to p53 with CRC risk, overall and by time between blood draw and diagnosis, was determined by conditional logistic regression. Results: Overall, 5% of controls and 7% of cases were sero-positive to p53, resulting in a statistically significant 33% increased CRC risk (OR: 1.33; 95% CI: 1.09, 1.61). The association was strongest for CRC diagnoses within 2 years after blood draw (OR: 2.73; 95% CI: 1.67, 4.45), with 15% sero-positive cases compared to 6% sero-positive controls. The number of sero-positive cases decreased with longer follow-up time (2–<5 years: 9%; 5–<10 years: 6%; ≥10 years: 3%) down to a proportion similar to that in controls resulting in the absence of an association of p53 sero-positivity with CRC risk after more than 5 years between blood draw and CRC diagnosis. Conclusion: In this large consortium of prospective cohorts, we found that pre-diagnostic sero-positivity to the tumor suppressor p53 was statistically significantly associated with a 2.7-fold increased risk of a subsequent CRC diagnosis within 2 years after blood draw, replicating the findings of the one previous cohort study examining this association. The findings suggest that while p53 sero-positivity may not be a useful predictor of long-term CRC risk, p53 auto-antibodies might be considered as part of a marker panel for early detection of this cancer.