Background: Many of the 50,000 annual colorectal cancer (CRC) deaths can be attributed to 1/3 eligible Americans not following screening guidelines or approximately 1/2 of the population not adherent to the follow-up post-polypectomy guidelines. The new understanding of the natural history and shared etiology of adenomas and CRC inform integration of clinically relevant biomarkers. The two objectives of CRC screening and surveillance are early detection to improve survival and prevention of CRC through removal of adenomas using colonoscopy. Adenomas account for 98% of actionable colonoscopies. Stool tests have low sensitivity for advanced adenomas (AA, 24-42%). Methods: A prospective, blinded study was conducted at the VA Palo Alto Health Care System. Patients had blood drawn prior to colonoscopy. The test analyzes two biomarkers: circulating gastrointestinal epithelial cells and somatic mutations of cell-free DNA. The probability of advanced neoplasia was obtained by ordinal/nominal logistic regression methods together with SEER-incidence rate and prior history of AA on a training set of 346 subjects. The cutpoint for the quantitative score was fixed and the remaining 112 subjects were tested. Results: Interim results for 458 patients with no prior diagnosis of colorectal cancer (CRC) are presented. The cohort included both screening (239) and surveillance (219) subjects. Indications for colonoscopy were 86% asymptomatic and 14% with symptoms or positive-FIT. Balanced distribution of roughly 3/4^th subjects in each disease category were randomly selected for training and algorithm development and the remaining 1/4^th subjects were used for validation. A cutpoint was selected to obtain a test specificity (non-neoplastic finding or negative colonoscopy) of 90% resulting in a sensitivity of 100% and 80.0% for detection of CRC and advanced neoplasia (AN = CRC+AA), respectively, on the training subjects. The area under the ROC curve is 0.91. Validation using the fixed cutpoint and 112 test subjects achieved 91.4% specificity and 100% and 75.0% sensitivity for CRC and AN. Conclusions: This blood test has high sensitivity for colorectal advanced neoplasia while retaining high specificity. The quantitative nature of the score has the potential to enable stratification of patients for screening or post-polypectomy surveillance colonoscopy.