OBJECTIVES: This study aims to compare the guaiac based Fecal Immunochemical Test (FIT), the primary colorectal cancer (CRC) detection technique, with the Fecal DNA (F-DNA) test which has been recommended as an alternative to FIT as the standard of care. METHODS: A hybrid decision tree-Markov model was created to estimate the CRC screening cost per quality adjusted life year (QALYs) of using the FIT annually, or the F-DNA every 3, or the F-DNA every 5 year in individuals at average CRC risk from a third party payer’s perspective. A hypothetical cohort of 10,000, 50 year old individuals transitioning between the health states: healthy, polyps <10mm, polyps>10mm, local cancer, regional cancer, advanced cancer, and dead, were followed until they were 75 years.  Colonoscopy followed every positive test result.  Sensitivity, specificity, transition probabilities, and costs (in 2010 US Dollars) were obtained from clinical trials and published peer-reviewed articles.  The costs and QALYs were discounted at 3% and sensitivity analyses were conducted. RESULTS: Using FIT annually would result in an average cost of $56,716.94/QALY for each individual with an incremental cost effectiveness ratio (ICER) of $76,181/QALY when compared to F-DNA used every 5 year. In the ICER plane of 1000 Monte Carlo simulations FIT was more costly but more effective technique compared to F-DNA used every 5 year, in 77% of the samples.  FIT was the most cost effective screening strategy at willingness to pay (WTP) of $100,000/QALY. However, at a lower WTP of $50,000/QALY, F-DNA every 5 year was cost effective until a threshold of $71,000/QALY. F-DNA conducted every 3 year was completely dominated by FIT. CONCLUSIONS: Further research is needed, and third party payers may need to assess variables such as compliance and patient characteristics, before considering the F-DNA as a standard of care for screening CRC.