Background: Identifying molecular residual disease (MRD) with tailored tumor-informed ctDNA-based next-generation sequencing (NGS) assays after curative surgery could facilitate the individualized management of resected colorectal cancer (CRC) patients. Here, we prospectively evaluated the clinical performance of tumor-informed ctDNA mutation analysis using a novel Burning Rock Patient-specific Prognostic and Potential Therapeutic Marker Tracking (brPROPHET) approach for assessing MRD in resected CRC patients. Methods: The brPROPHET assay was designed to track patient-specific somatic variants based on whole-exome sequencing (WES) of the tumor tissue and matched white blood cells (WBCs). Fixed panel with informed calling (FI) and fixed panel with agnostic calling (FA) assays were performed in a subset of patients with a 168-gene panel spanning 273 kb of the human genome for a head-to-head comparison. Results: A total of 117 patients (stage II/III 53[45.0%]/41[35.0%]) were analyzed. 60 (51.0%) patients were treated with adjuvant therapy after surgery. brPROPHET assay was designed to target up to 55 variants per patient. Only 6% (344/5835) of designed variants were included in the fixed panels. 75% (2908/3886) of genes selected for panel design were private to a specific patient. Preoperative ctDNA was detected in 97% (113/117) of the patients with 88% (14/16), 98% (52/53), 98% (40/41), and 100% (7/7) in stage I, II, III and IV, respectively. The median ctDNA levels were observed to be higher in patients with advanced stages and significantly correlated with tumor volume. MRD status was tested postoperatively on day 7 and day 30 with a positivity rate of 18% (21/117) and 15% (14/93), respectively. Due to a short follow-up period, only two patients had recurred, and ctDNA was detected prior to radiological relapse, with a lead time of 1 and 2 months, respectively. Among 74 patients enrolled for parallel comparing three MRD assays, preoperative ctDNA was detected in 97.3%, 75.7%, and 68.9% of patients with brPROPHET, FI and FA fixed panel assays, respectively. 20.3% (15/74) of patients had baseline ctDNA captured by brPROPHET assay only. The ctDNA levels of these patients (median:0.3 mean tumor molecules [MTM] / milliliter [mL]) were lower than those captured by FI/FA fixed panels (median:3.0 MTM/mL, p<0.05). A total of 135 postoperative blood samples were tested by all three assays, the positive rates with brPROPHET, FI and FA fixed panel assays were 14.8%, 8.1%, and 6.7% respectively. Conclusions: This initial study reported the clinical performance of the patient-specific brPROPHET assay in CRC, demonstrating superior sensitivity in detecting preoperative and postoperative ctDNA than the fixed panel assays. The ongoing study including correlation with clinical outcomes and serial testing will be presented.