Background: The presence of circulating antibodies to the p53 tumor suppressor protein is a potential early detection colorectal cancer biomarker. However, studies of prediagnostic measures of p53 seropositivity in relation to colorectal cancer risk are limited. Methods: We conducted a nested case–control study of serum p53 autoantibodies and risk of colorectal cancer within the Cancer Prevention Study-II Nutrition Cohort. Among cohort participants who were cancer free at the time of blood collection, 392 were subsequently diagnosed with colorectal cancer over 11 years of follow-up. Two controls were matched to each case on birth date, blood draw date, race, and sex. Autoantibodies to p53 were detected in 41 of the 392 cases (10.5%) and 49 of the 774 controls (6.3%). Results: Participants who were seropositive for p53 antibodies before diagnosis were more likely to be subsequently diagnosed with colorectal cancer [RR = 1.77; 95% confidence interval (CI), 1.12–2.78]. This association was strongest within 3 years of diagnosis (RR = 2.26; 95% CI, 1.06–4.83). An association was also suggested when colorectal cancer was diagnosed 4 to 〈6 years after p53 measurement (RR = 1.84; 95% CI, 0.89–3.79), but not 6 or more years later (RR = 1.15; 95% CI, 0.44–2.99). Conclusions: If these results are confirmed, serum p53 antibodies may be useful on a panel of early detection markers for colorectal cancer. Impact: Individuals who were seropositive for p53 antibodies were twice as likely to develop colorectal cancer within the next 3 years compared with those who were seronegative. This marker is a good candidate for inclusion on an early detection marker panel for colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(2); 219–23. ©2017 AACR .