Background: Annual computed tomography (CT) scans and periodic carcinoembryonic antigen (CEA) testing are monitoring methods for colorectal cancer (CRC) recurrence. We have previously described a 2-gene blood test for CRC (methylated BCAT1 and IKZF1) that may indicate tumour DNA shedding into the blood. The aim was to compare the 2-gene and CEA blood tests at detecting recurrence in CRC surveillance patients. Methods: Methylated BCAT1/IKZF1and CEA (positive ≥5ng/mL) were measured in patients previously diagnosed with CRC (excluding those undergoing active treatment). McNemar’s test was used for statistical analyses, using clinical findings including CT to diagnose recurrence. Results: At study midpoint, 340 patients were enrolled (64% men, average 64yr at diagnosis), including 59 patients with blood testing done pre- and post-resection, and 105 with CT surveillance scans (median 18 months after primary diagnosis). Following resection (median 2.3 months), 91% of patients who were 2-gene positive prior to treatment showed either no detectable methylated BCAT1/IKZF1(26/35) or significantly reduced levels in blood (6/35). Residual disease was found in two patients (2/3) who remained gene positive post treatment. Recurrence was identified in 30/105 (29%) patients with surveillance CT scans. Of these, 67% and 27% were 2-gene and CEA positive, respectively, with 8 (27%) cases positive by both tests (Table 1, p<0.001). In 13 cases with local recurrence, 54% were 2-gene positive, with only 1 (8%) positive by both tests (p=0.03). In 17 cases with distant recurrence, respective 76% and 41% were 2-gene and CEA positive (p=0.03). In patients with no evident disease, 20% were positive for one test but not the other (2-gene test, 16%; CEA, 4%; p = 0.04). Conclusions: Following resection, most patients had either reduced or no methylated BCAT1/IKZF1 in blood, indicating a correlation with the presence of cancer. Two-gene positivity correlated with local (54%) and distant (76%) recurrence with 2.5-fold more recurrence cases detected than with CEA. The 2-gene test may be better than CEA for recurrence monitoring.