Background: Numerous studies have shown the clinical utility of ctDNA, a non-invasive biomarker to detect MRD and stratify CRC patients who are more likely to relapse. We present an analysis of MRD detection in CRC patients from a prospective multicentre UK study, who were monitored pre- and post-surgery before adjuvant chemotherapy (ACT). Methods: The study recruited patients diagnosed with stage II-III CRC (n=122), including a subset of rectal patients who underwent tri-modality treatment (TMT). All patients had their primary tumor resected and 56% (68/122) received ACT. Paired plasma samples (n=244) were collected before surgery/neaodjuvant chemoradiotherapy and after surgery; median follow-up for survival was 15.48 months (0.16 - 42.1 months). Individual tumors and matched germline DNA were whole-exome sequenced and somatic single nucleotide variants (SNVs) identified. Multiplex PCR assays were designed to track tumor-specific SNVs (Signatera, bespoke mPCR NGS assay) in plasma samples. The study evaluated ctDNA status and clinical outcomes including radiologic imaging. Cox regression was used to calculate recurrence-free survival (RFS) in patients stratified by post-op ctDNA status. Patients were also stratified into low and high-risk groups based on the clinicopathological features. Multivariate analysis was performed with covariates: ctDNA, age, gender, laterality, stage, number of lymph node resected, MSI & TMB. Results: Pre-treatment ctDNA was detected in 93.4% (100/107) of patients. Post-operative ctDNA status prior to ACT was assessed in 107 patients, of whom, 13% (14/107) were MRD-positive (MRDpos). Of the MRDpos patients 42.9% (6/14) eventually relapsed. In contrast, only 8.6% (8/93) of MRD-negative (MRDneg) cases relapsed (HR: 10; 95% CI: 3.3-30; p<0.001). MRD rates stratified by risk features in each of the stages with respective recurrence rates are shown in Table. In stage III patients (n=64), 45.4% (5/11) of the MRDpos patients relapsed, whilst only 17% (9/53) of the MRDneg cases relapsed (HR: 9; 95% CI:2.6-32; p<0.0001). In the multivariate analysis, ctDNA status was the most significant prognostic factor associated with RFS (HR: 28.8, 95% CI: 3.5-234.1; p<0.001). Conclusions: Postoperative ctDNA analysis with tumor informed assay enables detection of CRC patients at high-risk of recurrence. Early detection of MRD could guide ACT decisions in intervention trials and is currently underway in TRACC. Clinical trial information: NCT04050345