Background: Clinical guidelines recommend surveillance for patients who complete primary treatment for colorectal cancer (CRC) with the aim of detecting recurrence when amenable to curative intent treatment. Currently recommended surveillance protocols, including imaging and CEA have limitations both in sensitivity and specificity, thus novel methods that detect circulating tumor DNA (ctDNA) have been introduced into clinical practice. COLVERA is a laboratory-developed, real-time PCR test that detects DNA methylation of BCAT1 and IKZF1 genes. These two genes are hypermethylated in 95% of CRC tissue and COLVERA showed improved sensitivity for detection of recurrent disease in comparison to CEA in several clinical populations. The current study evaluated the impact of optimizing the assay’s qualitative reporting method on actionability and clinical performance for recurrence detection in CRC surveillance setting. Methods: Two previously described cohorts of CRC patients (N=322 and N=144) who completed primary treatment and were undergoing surveillance were evaluated. Imaging and blood collections were performed at, or adjacent to, a standard of care visit. cfDNA was extracted from whole blood, bisulphite-treated and assayed in triplicates for BCAT1/IKZF methylation. Previously, any positive replicate of either target gene was reported as COLVERA “detected”. In the current study, COLVERA is “detected” when at least one replicate of IKZF1 or multiple replicates of either IKZF1 and/or BCAT1 are present. Sensitivity, specificity, and diagnostic odds ratio (DOR) for CRC recurrence detection from a single time-point blood sample was determined using radiological imaging as clinical reference standard. Results: In the first cohort (N=322), overall COLVERA test positivity was 6.5% (21/322) with a sensitivity of 59.3% (95% CI: 38.8 - 77.6) and specificity of 98.3% (96.1 - 99.5) for detecting recurrence at a time-point adjacent to imaging, representing improved specificity, from 91.5% (87.7 - 94.4%), with minimal decrease in sensitivity, from 63.0% (42.4 – 80.6). Similarly, in the second cohort (N=144) sensitivity was 62% (47.2 -75.4), compared to 66.0% (57.1 – 69.3) under the prior interpretation method, while specificity was 92.6% (85.3-97), compared to 90.4% (84.7 - 94.7). A high DOR of 84 (26 - 272) (previously 18 (7.6 – 44.4)) indicates that the revised COLVERA interpretation method is clinically more informative and differentiates with greater accuracy patients with and without the disease. Conclusions: This change in the COLVERA interpretation rule resulted in optimized clinical specificity with minimal impact on sensitivity. For an assay intended to aid in surveillance and early recurrence detection, improved accuracy allows the physician to have increased confidence in making actionable decisions based on test result, including further imaging or treatment.