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Tumor‐informed mutation‐based approaches are frequently used for detection of circulating tumor DNA (ctDNA). Not all mutations make equally effective ctDNA markers. The objective was to explore if prioritizing mutations using mutational features—such as cancer cell fraction (CCF), multiplicity, and error rate—would improve the success rate of tumor‐informed ctDNA analysis. Additionally, we aimed to develop a practical and easily implementable analysis pipeline for identifying and prioritizing candidate mutations from whole‐exome sequencing (WES) data. We analyzed WES and ctDNA data from three tumor‐informed ctDNA studies, one on bladder cancer (Cohort A) and two on colorectal cancer (Cohorts I and N). The studies included 390 patients. For each patient, a unique set of mutations (median mutations/patient: 6, interquartile 13, range: 1–46, total n = 4023) were used as markers of ctDNA. The tool PureCN was used to assess the CCF and multiplicity of each mutation. High‐CCF mutations were detected more frequently than low‐CCF mutations (Cohort A: odds ratio [OR] 20.6, 95% confidence interval [CI] 5.72–173, p = 1.73e−12; Cohort I: OR 2.24, 95% CI 1.44–3.52, p = 1.66e−04; and Cohort N: OR 1.78, 95% CI 1.14–2.79, p = 7.86e−03). The detection‐likelihood was additionally improved by selecting mutations with multiplicity of two or above (Cohort A: OR 1.55, 95% CI 1. 14–2.11, p = 3.85e−03; Cohort I: OR 1.78, 95% CI 1.23–2.56, p = 1.34e−03; and Cohort N: OR 1.94, 95% CI 1.63–2.31, p = 2.83e−14). Furthermore, selecting the mutations for which the ctDNA detection method had the lowest error rates, additionally improved the detection‐likelihood, particularly evident when plasma cell‐free DNA tumor fractions were below 0.1% (p = 2.1e−07). Selecting mutational markers with high CCF, high multiplicity, and low error rate significantly improve ctDNA detection likelihood. We provide free access to the analysis pipeline enabling others to perform qualified prioritization of mutations for tumor‐informed ctDNA analysis. [ABSTRACT FROM AUTHOR]