Background: An ongoing prospective study in patients with stage II or III colorectal cancer (CRC) has demonstrated ctDNA testing to be prognostic of recurrence risk and predictive of adjuvant chemotherapy (ACT) benefit. From the perspective of a US payer, we aimed to investigate the cost effectiveness of incorporating ctDNA analysis using the commercially available molecular residual disease (MRD) assay (Signatera™) into standard practice to aid in adjuvant chemotherapy decision-making, where traditional high-risk clinicopathological (CP) features have not shown a significant benefit of ACT in Stage II CRC. Methods: We developed a decision model to project lifetime clinical and economic consequences of different adjuvant treatment-guiding strategies. The model was parameterized using a follow-up of up to 2-years from a recently published data from GALAXY study and the cost data from the US literature. GALAXY is an observational arm of the ongoing CIRCULATE-Japan study (UMIN000039205) that analysed pre-surgical and post-surgical ctDNA in patients with stage II-IV resectable CRC. Costs are presented in 2023 US dollars. Future costs and benefits were discounted at 3%. Results: Compared to the CP predictors alone-based strategy, ctDNA analysis using the MRD assay in combination with CP predictors-based strategy led to an increase of 0.8 life years and 0.7 quality adjusted-Life Years (QALY) and cost savings of $9,771 per patient. Conclusions: The addition of MRD detection by ctDNA to traditional CP predictors aids in adjuvant chemotherapy decision-making in patients with stage II or III resectable CRC and is likely to be cost effective in the US healthcare system. ctDNA testing should therefore be considered for adoption in this disease setting.