Background: A considerable number of patients with stage II-III colon cancer experience disease recurrence following definitive treatment while others may receive unnecessary toxicity from adjuvant chemotherapy. Minimal residual disease (MRD) detection through ctDNA analysis can be evaluated without reliance on tissue which comes with logistic advantages and may be the only option for patients with limited tumor specimens. Methods: COSMOS-CRC-01 is an ongoing biomarker study that enrolled patients with resectable stage 0-III colorectal cancer between January 2020 and April 2021. Plasma samples and clinical data were collected 28 days post-operatively and every 3-6 months for up to 5 years alongside radiographic imaging. Samples were tested on the Guardant Reveal Infinity Oncology Platform for MRD detection. This analytically validated multiomic NGS assay interrogates >700 genes and ~15Mb of methylated regions. A bioinformatics algorithm trained for CRC detection classifies each sample as ctDNA detectable or undetectable based on a predefined statistical likelihood threshold and returns quantitative tumor fraction. The primary endpoint was time to recurrence (TTR) based on ctDNA detection status. Results: This subgroup analysis evaluated 801 post-surgical plasma samples (4mL each, median input 19ng, 96% passed QC) from 136 patients with R0 resected stage II-III colon cancer with a median follow-up of 28 months. ctDNA detection at Day 28 post-surgery and following adjuvant chemotherapy were both associated with significantly shorter TTR (p<0.0001; Table). Sensitivity with serial measurement was 80% (95% CI, 56.3-94.3%), with a median lead time of 5.3 months. Sensitivity was highest for detection of locoregional (2/2), brain (1/1), liver (7/7), or multiple (3/3) metastasis compared to isolated lung (2/4) or peritoneal (1/3) metastasis. Tumor fraction increased as expected in samples collected closer to the time of radiographic detection. Three recurred patients had KRAS G12C variants detected in ctDNA prior to recurrence, suggesting the potential of early intervention with targeted agents. Among 553 post-treatment samples from 114 non-recurred patients, sample specificity was 97.3% (95% CI 95.6-98.5%). Conclusions: We show a plasma-only genomic- and methylation-based assay to have sensitive and specific detection of MRD in stage II-III colon cancer. Serial measurement provides superior performance versus one-time measurement at Day 28 post-surgery and detects targetable variants prior to recurrence.