Our findings show that detection of methylated BCAT1, IKZF1 and IRF4 in circulating ccfDNA differentiates cases with CRC from those without neoplasia, and that the specificity of the multi-target assay can be substantially improved with no significant effect on sensitivity by applying a PCR replicate rule to BCAT1. This panel of markers should now be prospectively evaluated in a typical screening population to clarify accuracy of different marker configurations against that of FIT. Here, IRF4 is linked to neoplasm.