Background: The methylated ctDNA biomarkers BCAT1 and IKZF1 are common events in colorectal cancer (CRC), play a role in its development and drugs targeting BCAT1 are available. As these biomarkers disappear from blood after surgery in most patients, a prospective study was conducted to assess the relationship between their persistence post-surgery and presence of and risk for residual disease as well as survival. Methods: ctDNA status using these biomarkers was determined within 12 mo of initial surgical resection. Detection of either marker was related by logistic regression and survival analysis (Cox proportional hazards) to pathologically-determined presence or risk of residual disease (“RD”, margins involved, metastases present or nature of node involvement) and to recurrence-free survival. Results: 172 CRC patients were tested for the biomarkers and then followed for a median 37.1mo (IQR 22.6-49.8) during which 23 experienced recurrence and 10 died from CRC. 28 (16%) were ctDNA positive post-surgery. Univariate analysis showed that a positive result was more likely if any of three markers of RD was present (OR 7.7, 95% CI: 2.3-25.0 p = 0.001); while increasing number of lymph nodes (OR 8.3, 95% CI: 1.8-37.7 p = 0.004) and involved peritoneum (OR 3.8, 95% CI: 1.6-9.2 p = 0.003) where also associated with a positive result. Multivariate modelling with adjustment for treatment status at time of venesection indicated that features of RD was an independent predictor of post-surgery ctDNA status: cases with 3 features (margins or apical node involved, distant metastases) were 5.3 times (95% CI: 1.5-18.4, p-value = 0.008) more likely to be positive. Modelling recurrence-free survival showed that post-surgery ctDNA positivity was associated with an increased risk of recurrence (HR 3.8, 1.5-9.5, p = 0.004). Conclusions: CRC cases positive for these ctDNA biomarkers within 12 months of surgery are at increased risk of residual disease and subsequently for recurrence. This has implications for adjuvant therapy and monitoring of cases; randomised studies are now indicated to determine if such can provide survival benefit. Clinical trial information: 12611000318987.