BACKGROUND: Colorectal cancer (CRC) is a major cause of morbidity and mortality in France. Only scanty data on cost-effectiveness of CRC screening in Europe are available, generating uncertainty over its efficiency. Although immunochemical fecal tests (FIT) and guaiac-based fecal occult blood tests (g-FOBT) have been shown to be cost-effective in France, cost-effectiveness of endoscopic screening has not yet been addressed. METHODS: Cost-effectiveness of screening strategies using colonoscopy, flexible sigmoidoscopy, second-generation colon capsule endoscopy (CCE), FIT and g-FOBT were compared using a Markov model. A 40 % adherence rate was assumed for all strategies. Colonoscopy costs included anesthesiologist assistance. Incremental cost-effectiveness ratios (ICERs) were calculated. Probabilistic and value-of-information analyses were used to estimate the expected benefit of future research. A third-payer perspective was adopted. RESULTS: In the reference case analysis, FIT repeated every year was the most cost-effective strategy, with an ICER of €48165 per life-year gained vs. FIT every 2 years, which was the next most cost-effective strategy. Although CCE every 5 years was as effective as FIT 1-year, it was not a cost-effective alternative. Colonoscopy repeated every 10 years was substantially more costly, and slightly less effective than FIT 1-year. When projecting the model outputs onto the French population, the least (g-FOBT 2-years) and most (FIT 1-year) effective strategies reduced the absolute number of annual CRC deaths from 16037 to 12916 and 11217, respectively, resulting in an annual additional cost of €26 million and €347 million, respectively. Probabilistic sensitivity analysis demonstrated that FIT 1-year was the optimal choice in 20% of the simulated scenarios, whereas sigmoidoscopy 5-years, colonoscopy, and FIT 2-years were the optimal choices in 40%, 26%, and 14%, respectively. CONCLUSIONS: A screening program based on FIT 1-year appeared to be the most cost-effective approach for CRC screening in France. However, a substantial uncertainty over this choice is still present.