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Background: DNA methylated in BCAT1 and IKZF1 are promising circulating tumor DNA (ctDNA) biomarkers for colorectal cancer detection. This study tested for variables that might be associated with their detection in patients without colonoscopically evident colorectal cancer so-called false positives., Methods: A retrospective review of demographic and clinical variables was conducted on patients who were assayed for these biomarkers prior to a colonoscopy for any indication. Potential relationships between detection of these biomarkers and patient variables in patients without colorectal cancer were identified by logistic regression. An age- and sex-matched case-control study was undertaken to identify additional associations., Results: A total of 196 of 1,593 patients undergoing colonoscopy were positive for BCAT1 and/or IKZF1 methylation; 70 (35.7%) had confirmed diagnosis of colorectal cancer. Of the 126 false positives, biomarker levels were significantly lower than in those with colorectal cancer ( P < 0.05), with the total cell-free circulating DNA concentration associated with biomarker detection (OR, 1.16; 95% CI, 1.10-1.22), and 83 (65.9%) of the non-colorectal cancer cases positive for methylated BCAT1 only. Age ≥70 years was the only demographic variable associated with biomarker detection (OR, 4.31; 95% CI, 1.50-12.41). No significant associations were seen with medications or comorbidities ( P > 0.05). Four cases without colonoscopically evident colorectal cancer but with biomarker levels above the median for patients with colorectal cancer were diagnosed with metastatic adenocarcinoma within 1 year., Conclusions: False-positive results were most commonly associated with detection of methylated BCAT1 only, as well as age ≥70 years., Impact: In the absence of colonoscopically evident colorectal cancer, a high level of circulating methylated DNA warrants investigations for cancers at other sites., (©2021 American Association for Cancer Research.)