Background: Use and impact of circulating tumor DNA (ctDNA) testing for MRD detection has been infrequently reported outside clinical trials. We report clinical use of a validated plasma-only multi-omic MRD assay in a large, unselected CRC cohort, including clinically annotated cases. Methods: The first 2,000 US patients (pts) with documented stage (stg) and Guardant Reveal MRD test results since clinical launch in Feb 2021 were queried; all tests per pt were analyzed (data cut-off: July 2022). Pts could be enrolled in a post-operative program (POP, up to 3 tests 3-16 weeks post-resection) or a surveillance program (SP, after treatment) for recurrent tests; pts could also have one-time tests. Programs were analyzed for stg II/III only. Clinical factors were extracted from test requisition forms; pts from Siteman Cancer Center had additional data extracted from medical records. Results: 1994 pts met criteria for analysis with median age of 64 (range 21-95); 1,112 (56%) were male. ctDNA was detected in 27%, with detection increasing by stg (Table). 30% of positive samples were detected by methylation only, a 43% increased detection over genomic only analysis. 505/544 positive pts had >1 test: 20% had ctDNA first detected on a subsequent test, a 25% increase when testing serially. Most stg II/III pts were tested in the SP. Stg II pts tested POP had a median turnaround time of 10 days (range 6-42); 96% had results prior to 12 weeks post-resection. In the annotated subgroup of 28 pts (65 tests), 8/28 (28%) had ctDNA detected. 13 pts had rectal- and 15 had colon cancer. 11/28 (39%) were stg II, 13 (46%) stg III, 4 (14%) stg IV. 26/28 had surgery, 7/13 rectal pts had neoadjuvant chemotherapy and/or radiation prior to ctDNA testing. 8 (29%) pts recurred. At data cut-off, assay sensitivity to predict or confirm recurrence was 80% (95%CI: 44.4-97.5%), specificity 100% (95%CI: 81.5-100%), PPV 100%, NPV 90% (95%CI:72.26-96.9%). Two pts with recurrence and negative ctDNA had their last test >6 months prior to recurrence. Testing informed clinical decision-making in 11 (39%) pts to proceed with systemic therapy (5), repeat scans sooner (2), proceed with biopsy (1), or confirm recurrence (3). Conclusions: Through real-word data, we confirm prior studies showing multi-omic plasma-only MRD testing has high sensitivity and specificity for recurrence and now show use of the assay in clinical decision-making. Notably, methylation analysis and serial testing both improved detection of MRD and impacted clinical care. These findings should continue to be studied in larger cohorts and randomized trials.