Background: Over half of patients (pts) with oligometastatic CRC treated with curative intent surgery or radiotherapy experience cancer recurrence with or without adjuvant chemotherapy. ctDNA detection post-definitive treatment could identify high risk pts for additional intervention to eliminate molecular residual disease. Here we report results of a prospective observational study aiming to determine ctDNA detection rates using a sensitive liquid biopsy and to correlate post-procedure ctDNA detection (post-ctDNA (+)) with radiographic mCRC recurrence. Methods: Pts with mCRC intending to undergo a curative intent procedure were prospectively recruited at two US sites. ctDNA was collected pre-procedure, 3 weeks post-procedure, and at multiple structured follow-up timepoints. The presence of ctDNA was evaluated using a plasma-only integrated genomic and epigenomic assay (Guardant Reveal, Guardant Health). A bioinformatic classifier was applied to differentiate tumor derived versus non-tumor derived cell-free DNA. Results: Among 52 enrolled pts, post-ctDNA data is available for 45 pts (87%), with a median of 4 (range 1-10) timepoints per pt. The sample analysis failure rate was 1% (2/217). As of 1/1/2021, the radiographic recurrence rate was 60% with a median follow-up time of 50 (range 4-192) weeks. 23 of 25 pts with post-ctDNA(+) have had recurrence (Positive Predictive Value [PPV], 92%). On average, ctDNA was detected 28 weeks before radiographic recurrence (mean 12 vs. 40 weeks, respectively). The two pts with post-ctDNA(+) but no recurrence have > 3 years follow-up; one pt received adjuvant chemotherapy and cleared ctDNA. With a median event-free follow-up time of 97 (range 4-192) weeks, 4 of 20 pts with no post-ctDNA detection (-) have recurred (Negative Predictive Value, 80%). 3 of 4 pts with recurrence despite post-ctDNA(-) also were pre-ctDNA(-). We observed a sensitivity of 85% and a specificity of 89% for the ctDNA assay. The median time to radiographic recurrence was 36 wks for ctDNA(+) vs. not reached for ctDNA(-) (Hazard Ratio, 7.7; 95% CI, 2.6-22.5; P<.001). Conclusions: In mCRC pts undergoing curative intent surgery or radiotherapy, detection of ctDNA post-procedure had a high PPV for cancer recurrence, with a median lead time of 6 months compared to surveillance imaging. Thus, ctDNA holds promise as a biomarker for pt enrollment on clinical trials and as an endpoint for monitoring of response to experimental therapies in this oligometastatic CRC population.