Background: Patient risk for recurrence after completion of initial treatment of colorectal cancer (CRC) is difficult to predict. Post-treatment circulating tumor DNA (ctDNA) analysis is a promising approach for stratifying such patients but the value of using tumor-uninformed biomarkers, such as methylated BCAT1 and IKZF1, is unknown. This study aimed to determine whether detection of circulating methylated BCAT1 and IKZF1 DNA following completed initial treatment with curative intent, identified patients at elevated risk of CRC recurrence. Methods: CRC stage I-III cases were eligible for study inclusion if a BCAT1/IKZF1 methylation test result was available at least 2 weeks after, but within 12mo, of completing initial treatment, and had had at least 2y follow-up unless recurrence was evident sooner (n = 142). Surveillance included regular clinical assessments and radiographic imaging. Level of methylation was reported as the total methylated BCAT1/IKZF1 expressed as percent of cell-free DNA; levels ≥0.07% were considered positive. Primary outcome measure was recurrence-free survival. Mantel-Cox (logrank) method was used to assess the association between BCAT1/IKZF1 results and recurrence-free survival. Multivariable survival analysis by Cox proportional hazards modelling assessed the impact of covariates, including: BCAT1/IKZF1 result, age, gender, T-stage (T1-2 vs T3-4), N-stage (N0 vs N1-2), extra- and/or intra-mural vascular invasion (EMVI/IMVI) and nature of treatment. Time to recurrence was measured from the date of treatment completion to first evidence of recurrence and data were censored to last date of follow-up. Results: 33/142 (23.2%) cases had recurrence detected at a median 1.6y (IQR: 0.8-2.4). Follow-up time for those who remained recurrence free was 5.3y (IQR: 3.7-6.9). The time between completing treatment and BCAT1/IKZF1 testing was not different between these groups (median 2.4 vs 3.1mo, p = 0.530). 13 (9.2%) cases were positive for methylated BCAT1/IKZF1 after completing treatment and a positive result was associated with a significant risk of recurrence (hazard ratio [HR], 10.0 (95%CI 2.6-39.3), p < 0.001). In the multivariable survival analysis, only a positive BCAT1/IKZF1 methylation result following treatment (HR 2.6, 95%CI: 1.0-6.0, p = 0.041) and evidence of EMVI or IMVI (HR 2.3, 95%CI: 1.0-5.1, p = 0.044) were significant predictors of survival. Conclusions: This study shows that post-treatment BCAT1/IKZF1 methylation testing, which does not need personalization using tumor genotyping, is a promising independent prognostic indicator for CRC recurrence. Such cases are at high risk of recurrence compared to those who had no detectable ctDNA post treatment. These patients warrant enhanced and/or extended surveillance for recurrence. Clinical trial information: 12611000318987.