OBJECTIVES: DNA Stool testing for early detection of colorectal cancer (CRC) is a non-invasive technology possibly supplementing established stool tests. This health technology assessment (HTA) assesses effectiveness and safety of two stool DNA tests currently CE-marked, compared to several other screening tests within an asymptomatic screening population. METHODS: Methods followed the guidelines of the European Network for Health Technology Assessment (EUnetHTA). This included systematic literature search in Medline, Cochrane, EMBASE. Manufacturers were contacted for submitting data. Risk of bias was assessed using QUADAS-2, quality of the body of evidence using GRADE. Five patients were interviewed during scoping phase. RESULTS: Three test accuracy studies were identified: Two investigate a multitarget stool DNA test (MSDT, Cologuard®, comparing to two FITs), one a combined stool DNA test (CSDT, ColoAlert®, comparing to gFOBT, M2-PK, gFOBT/M2-PK). No primary studies investigating effects on CRC or overall mortality were found. A Markov state-transition cohort model was developed to assess benefits and harms of five screening strategies. None of the primary studies reported adverse events or investigated consequences out of false positive or false negative test results from the viewpoint of patient safety. Full results of this HTA are published on the EUnetHTA website. CONCLUSIONS:The two DNA stool tests represent products in a series of research developments that consistently try to find better markers / analytical algorithms for the detection of CRC / precancerous lesions with a non-invasive screening test. European screening programs at the moment do not include DNA stool testing, nor is it reimbursed. Because of disease progression and prognosis the main target for these tests is to yield a positive test in persons with advanced adenomas or CRC. It may be discussed if the tests also should - preferably - yield a positive result (and colonoscopy reference) in case of non-advanced adenomas. Also test failure rates are a relevant issue.