Background: Routine screening methods for colorectal cancer (CRC) have poor patient compliance and low sensitivity for early stages. The sensitivity rates are 19, 71, 76, and 83% for Fecal Occult Blood test (FOBT), stool DNA test, colonoscopy/sigmoidoscopy, and double-contrast barium enema; respectively. Biological markers have also been tested including CEA (sensitivity of 38.7%); however, its utility in CRC screening is limited due to low sensitivity. Onko-Sure is an FDA-cleared blood test for monitoring of CRC treatment/recurrence. It measures the accumulation of Fibrin/Fibrinogen Degradation products in the serum using anti-DR-70 antibody. The objective was to determine whether DR-70 and CEA combination can improve the sensitivity such that it can be used as a cost-effective alternative to current screening methods yet with a higher patient compliance. Methods: A total of 564 serum samples were retrospectively obtained from a serum bank in two arms: confirmed healthy control (n=298) and biopsy-confirmed CRC (n=266) groups. The samples were tested for DR-70 and CEA. Results: The results showed sensitivity of 58.2% and specificity of 59.83% for DR-70 and CEA combined. The sensitivity for the combined test was 55.5% higher than that of CEA alone. A consistent improvement of sensitivity for the combined usage relative to CEA alone was observed with an increase of 73%, 108%, 58% and 18% in CRC stage I, II, III and IV; respectively. The sensitivity of the combined test was 48%, 47%, 57% and 98% for stages I, II, III and IV. Conclusions: Combining DR-70 and CEA tests showed a significant clinical advantage in CRC screening over using each marker alone. The sensitivity improvement was highest for stages I/II, which has important implications in patient treatment options, prognosis and survival rate due to this early detection. With a 3 times higher sensitivity for early stage CRC compared to using FOBT, this approach should improve the CRC early stage diagnosis. Such early stage detection is less likely using routine approaches for CRC screening because of low sensitivity and low patient compliance.