BACKGROUND: To compare cost-effectiveness of 3 novel non-invasive tests (multitarget stool RNA (mt-sRNA), multitarget stool DNA 2.0 (mt-sDNA 2.0), and cell-free DNA (cf-DNA)) with guideline-recommended tests for colorectal cancer (CRC) screening from payer's perspective. METHODS: Outcomes of a hypothetical cohort of 100,000 individuals aged 45-year-old with average CRC risk (no prior CRC diagnosis, adenomatous polyps, or other disorders associated with a high lifetime risk of CRC) in the US were simulated by a lifelong Markov model. Screening strategies included: Guideline-recommended strategies (colonoscopy, flexible sigmoidoscopy, computed tomographic colonography, fecal immunochemical test, high-sensitivity guaiac-based fecal occult blood testing, multitarget stool DNA), 3 novel non-invasive tests, and no screening. Scenario analyses on perfect (100%) and test-specific adherence (reported real-world adherence) were conducted. Outcomes included direct cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: All screening strategies (versus no screening) reduced CRC cases and deaths. In perfect adherence scenario, every-10-year colonoscopy was the preferred strategy (ICER=US61/QALY). In test-specific adherence scenario, every-3-year mt-sRNA was the preferred cost-effective strategy (ICER=US5,250/QALY). Testing cost, performance, adherence, and CRC prevalence, progression rate and utility were influential factors. Every-3-year mt-sRNA showed the highest probability (37.6%) to be cost-effective in test-specific adherence scenario at willingness-to-pay US00,000/QALY. CONCLUSIONS: All strategies were cost-effective compared to no screening. Every-3-year mt-sRNA (preferred strategy in real-world adherence scenario) provides a cost-effective alternative when adherence to CRC screening or follow-up was not perfect in clinical practice. IMPACT: This is the first study to demonstrate cost-effectiveness of novel non-invasive tests versus all guideline-recommended CRC screening tests.