Background: Adjuvant chemotherapy (ACT) is routinely offered to patients with high risk (HR) stage II or stage III CRC following potentially curative surgery. Over 50% of stage III and > 80% of stage II patients are cured by surgery alone but are being exposed to unnecessary chemotherapy with short- and long-term side effects. Post-operative ctDNA identifies minimal residual disease (MRD) after surgery in CRC. Our national study, TRACC, compares ctDNA guided versus standard of care (SoC) decision making in patients undergoing ACT. Methods: This is a UK-wide, multi-centre, prospective, two-arm, randomised trial. Patients with HR risk stage II or stage III CRC who have undergone R0 resection and have detectable ctDNA in their pre-surgical sample are eligible. Patients who undergo neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer with detectable ctDNA pre-CRT are also eligible. Patients are randomised in a 1:1 ratio to receive either SoC ACT or ctDNA guided ACT. In the ctDNA guided arm, patients who are ctDNA negative post-operatively have chemotherapy de-escalated i.e., 3 months(m) of Capecitabine and Oxaliplatin (CAPOX) doublet ACT is reduced to 3 m single agent Capecitabine; 6 m single agent Capecitabine reduced to no chemotherapy. In this group, ctDNA is re-tested at 3 months and if detectable, patients receive 3 months of CAPOX. Primary end-point is 3-year disease free survival (DFS). Secondary end-points include overall survival, neurotoxicity, quality of life and health economics. Based on a standard 3-year DFS of 75% in SoC ACT arm, to demonstrate a non-inferiority margin of 1.25, 810 patients are required per arm (85% power, α = 0.1). Stratification is by tumour staging and site of primary tumour. Target accrual is over 4 years. The study opened to recruitment in January 2020 and is supported by the MRC-NIHR Efficacy and Mechanism Evaluation Grant (NIHR128529). Clinical trial information: NCT04050345.