Background: The role of adjuvant chemotherapy (CT) in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival (RFS), while its absence predicts a low recurrence risk. For ctDNA-positive cases the benefit of adjuvant CT is unknown. DYNAMIC was designed to assess if a ctDNA-guided approach could reduce the use of adjuvant CT without compromising recurrence risk. Methods: DYNAMIC is a multi-center randomized controlled phase II trial. Eligible patients had resected stage II colon cancer and were suitable for adjuvant CT. Patients were randomly assigned 2:1 to ctDNA-guided management or standard management (clinician-guided based on conventional criteria), after stratification for T stage and participating center location. Criteria for clinical low versus high risk were predefined. The Safe-SeqS tumor-informed personalized ctDNA assay was used. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine CT; ctDNA-negative patients were not treated. The primary efficacy endpoint was non-inferiority in RFS rate at 2 years. A key secondary endpoint was adjuvant CT use. The target sample size of 450 provided 80% power with 95% confidence to confirm non-inferiority between the two arms with a margin of 8.5%. Results: Of 455 patients randomized between Aug 2015 and Aug 2019, 302 were assigned to ctDNA-guided and 153 to standard management. Median follow-up was 37 months. In the ctDNA-guided arm, ctDNA analysis was successful in all but three patients; only two patients did not receive ctDNA-guided management. In the intention to treat population, fewer patients overall in the ctDNA-guided arm received adjuvant CT compared to standard management (15.3% vs 27.9%, odds ratio 2.14; P = 0.002), with the largest difference seen in patients with T4 or poorly differentiated tumors (odds ratios 6.22 and 6.31, respectively). Of those who received treatment, oxaliplatin-based doublet was more frequently administered than fluoropyrimidine alone for ctDNA-guided compared to standard management patients (62.2% vs. 9.8%; P < 0.001). ctDNA-guided management was non-inferior to standard management for 2-year RFS (93.5% vs 92.4%, difference 1.1%, 95% confidence interval, -4.1% to 6.2%). Following adjuvant CT, 3-year RFS for ctDNA-positive patients was 86.4%. Without adjuvant CT, 3-year RFS for ctDNA-negative patients was 92.5%, with a 3-year RFS of 96.7% in the clinical low risk subgroup. Conclusions: A ctDNA-guided approach to stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. The low recurrence rate in ctDNA-positive patients who received chemotherapy suggests a survival benefit from adjuvant therapy. ctDNA-negative patients are unlikely to benefit from chemotherapy. Clinical trial information: ACTRN12615000381583.