Abstract Omentin is a novel biomarker shown to exert metabolic, inflammatory, and immune-related properties and thereby could be implicated in the risk of colorectal cancer. So far, the association between omentin and colorectal cancer risk has not been evaluated in prospective cohort studies. We investigated the association between prediagnostic plasma omentin concentrations and risk of colorectal cancer in a case–cohort comprising 251 incident colorectal cancer cases diagnosed over a mean follow-up time of 10.4 years and 2,295 persons who remained free of cancer in the European Prospective Investigation into Cancer and Nutrition-Potsdam study. Hazard ratios as a measure of relative risk (RR) and 95% confidence intervals (CI) were computed using a Prentice-modified Cox regression. In a multivariable model adjusted for age, sex, education, dietary and lifestyle factors, body mass index (BMI), and waist circumference, higher omentin concentrations were associated with a higher colorectal cancer risk (RRcontinuously per doubling of omentin concentrations = 1.98; 95% CI, 1.45–2.73). Additional adjustment for metabolic biomarkers, including glycated hemoglobin, high-density lipoprotein cholesterol, and C-reactive protein, did not alter the results. In stratified analyses, the positive association between omentin and colorectal cancer risk was retained in participants with BMI < 30 (RRcontinuously per doubling of omentin concentrations = 2.26; 95% CI, 1.57–3.27), whereas among participants with BMI ≥ 30 no association was revealed (RRcontinuously per doubling of omentin concentrations = 1.07; 95% CI, 0.63–1.83; Pinteraction = 0.005). These novel findings provide the first lines of evidence for an independent association between prediagnostic omentin concentrations and colorectal cancer risk and suggest a potential interaction with the adiposity state of the individual. Cancer Res; 76(13); 3862–71. ©2016 AACR.