Background: About 30-50% colorectal cancer patients undergoing a curative resection will experience disease recurrence ultimately. Early detection of recurrence is of great significance for improving the prognosis of colorectal cancer patients. Circulating tumor DNA (ctDNA) has been suggested to be a promising biomarker for postoperative surveillance and prognosis prediction in various cancers including colorectal cancer. However, its performance in predicting early recurrence of colorectal cancer as well as appropriate testing procedures still needs large-scale prospective studies to evaluate. Methods: A total of 246 patients with stage II-III colorectal cancer and underwent curative resection from three clinical centers of China were enrolled in this multicenter prospective cohort study. Tissue samples as well as serial plasma samples before surgery, 7 days and 6 months after surgery and 3 months interval afterwards until recurrence were collected, and subjected to deep targeted-panel sequencing containing 425 cancer-related genes. ctDNA baseline genomic alterations and dynamic changes were analyzed. Its performance in predicting early recurrence was evaluated and compared with other clinical routine investigations, including serum biomarkers CEA and CA199, and CT examination. Results: The ctDNA positive rates at baseline (before surgery) and 7 days after surgery were 72.9% and 18.1% respectively. Among 199 patients with complete survival data, 18 patients were recurrent during follow up period with a median disease-free survival of 280.5 days (114-461 days). At baseline, high clinical stage (p = 0.035), and PTEN mutation (p = 0.009) were significantly associated with increased recurrent risk; while APC mutation (p = 0.04) predicted a decreased recurrent risk. Detection of ctDNA 7 days after surgery [HR: 5.9 (1.94-17.97); p = 0.0004] or any time point before clinical recurrence [HR: 6.14 (2.3-16.38); p < 0.0001] was associated with a significantly higher recurrent risk, and the HR increased accordingly with ctDNA mutation level. In multivariate analyses, ctDNA status was independently associated with relapse after adjusting for known clinicopathological risk factors. CEA status was not significantly (p > 0.4) associated with disease-free survival. A risk scoring model comprising of clinical variables and ctDNA detection after surgery was constructed and can predict 18-month recurrence with an AUC of 0.77. Conclusions: ctDNA is a promising marker of risk stratification, and early relapse detection in resected stage II/III CRC patients. Clinical trial information: NCT03312374.