Background: Signatera (S) assay is a CLIA certified minimal residual disease ctDNA assay that has become widely used for monitoring of disease relapse in patients (pts) with resected colorectal cancer. In a longitudinal study, S+ recurrence (SR) occurred at median > 10 months (mo) prior to radiographic disease recurrence (RDR) in a prospective clinical trial. However, the radiographic surveillance frequency in that study was inadequate by US standard practices. Methods: We retrospectively evaluated, in a single center, the sensitivity (ss), specificity (sp), positive predictive value (ppv) and negative predictive value (npv) of S, CT/MRI imaging (Im), and CEA in curatively resected stage II, III, IV pts against True Disease Recurrence (TDR). We considered TDR as any SR, RDR confirmed by pathology, RDR associated with CEA elevation, or RDR with sequential growth on imaging or regression with chemo. S and CEA were performed Q3 mo x 2 yrs and then Q6 mo x 3 yrs. Im was performed Q3 mo x 2 yrs and then Q6 mo x 3 yrs in resected stage IV, Q6 mo x 2 yrs and then Q yr x 3 in stage III/high-risk stage II, and Q yr x 5 yrs in low-risk stage II. Results: 48 pts underwent curative resection (31 stage II-III, 17 stage IV). 15 patients recurred during surveillance (6 stage II-III, 9 stage IV). The ss, sp, ppv, and npv of S, Im, CEA, and (Im and/or CEA) are tabulated below. S, Im, CEA, and Im or CEA were positive for recurrence at the diagnosis of TDR in 8, 9, 4, and 12, respectively. S sensitivity was poor for lung recurrence with 5/6 pts with lung-only mets (3 confirmed by path) being negative by S at the time of Im relapse. S was negative at the time of CNS recurrence and liver recurrence in 2 pts. 2 Pts with negative imaging at SR developed subsequent liver metastases. 2 Pts, counted as TDR, were SR and remain NED without any therapy, by CEA and Im > 1.5 years from S positivity. Conclusions: S does not appear to provide definitive advantages as a surveillance strategy over standard Im frequency- when performed as per NCCN guidelines. Sensitivity of S is particularly poor for low volume lung-only disease recurrence.