Background: Postoperative circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) is reported to be associated with a high risk of recurrence. Here, we present an updated analysis of MRD detection and correlations with BRAF and MSI status in radically resected, stage II-IV colorectal cancer (CRC) from the observational GALAXY study (UMIN000039205). Methods: Serial ctDNA was analyzed using personalized tumor-informed assay (Signatera bespoke multiplex-PCR NGS assay) at 1 (4-week MRD time point), 3, 6, 9, 12, 18, and 24 months after surgery or until recurrence (whichever comes first). CT scans were conducted every 6 months. BRAF and MSI status were determined by central assessment until September 2021 and per the standard of care after October 2021. The primary endpoint was disease-free survival (DFS), defined as the time between the date of surgery and date of diagnosis with relapse or death due to any cause. Results: Among 3,615 CRC patients (pts) who were enrolled between May 2020 and April 2022 in GALAXY study, 2,083 pts that met the inclusion criteria were analyzed. The median follow-up period was 16.3 months. Of 2,083 pts included in the analysis, 60 pts (2.9%) had BRAF V600E mutant and MSS tumors, 100 pts (4.8%) had BRAF wt and MSI-H tumors, and 115 patients (5.5%) had BRAF V600E mutant and MSI-H tumors. In the overall population, 286 (14%) were ctDNA-positive at the 4-week MRD time point and 1,797 (86%) were ctDNA-negative. Pts with ctDNA-positivity at the 4-week demonstrated inferior DFS and were 12 times more likely to recur, compared to ctDNA-negative pts (HR: 12, 95%CI: 9.1-15%; p<0.001). Pts with BRAF wt and MSI-H tumors had significantly better DFS compared to pts with BRAF wt and MSS tumors (HR: 4.14, 95 %CI: 1.3-12.9, p=0.015). Pts with BRAF V600E mutant and MSI-H tumors had significantly better DFS compared to pts with BRAF wt and MSS tumors (HR: 4.80, 95 %CI: 1.5-15, p=0.007). On the other hand, ctDNA-positivity was associated with significantly shorter DFS in pts with BRAF V600E mutant and MSS tumors (HR: 2.33, 95%CI: 1.03-5.3, p=0.043) and BRAF V600E mutant and MSI-H tumors (HR:7.54, 95%CI:2.37-24, p<0.001) compared to pts with BRAF wt and MSS tumors. Multivariate analysis in DFS showed that ctDNA positivity was significantly associated with poor prognosis (HR: 11.68, 95%CI: 8.61-15.85, p<0.001), outperforming other clinicopathologic factors such as BRAF and MSI status. Conclusions: ctDNA status at the postoperative MRD time point is the most prognostic risk factor of DFS regardless of BRAF V600E or MSI-H status. Pts with positive postoperative ctDNA should be examined carefully due to a high risk of recurrence. ctDNA-guided adjuvant strategies will further be established by the ongoing randomized VEGA and ALTAIR studies in CIRCULATE-Japan. Clinical trial information: UMIN000039205.