Colorectal cancer (CRC) screening guidelines recommend screening schedules for each single type of test except for concurrent sigmoidoscopy and fecal occult blood test (FOBT). We investigated the cost-effectiveness of a hybrid screening strategy that was based on a fecal immunological test (FIT) and colonoscopy. We conducted a cost-effectiveness analysis by using the Archimedes Model to evaluate the effects of different CRC screening strategies on health outcomes and costs related to CRC in a population that represents members of Kaiser Permanente Northern California. The Archimedes Model is a large-scale simulation of human physiology, diseases, interventions, and health care systems. The CRC submodel in the Archimedes Model was derived from public databases, published epidemiologic studies, and clinical trials. A hybrid screening strategy led to substantial reductions in CRC incidence and mortality, gains in quality-adjusted life years (QALYs), and reductions in costs, comparable with those of the best single-test strategies. Screening by annual FIT of patients 50-65 years old and then a single colonoscopy when they were 66 years old (FIT/COLOx1) reduced CRC incidence by 72% and gained 110 QALYs for every 1000 people during a period of 30 years, compared with no screening. Compared with annual FIT, FIT/COLOx1 gained 1400 QALYs/100,000 persons at an incremental cost of $9700/QALY gained and required 55% fewer FITs. Compared with FIT/COLOx1, colonoscopy at 10-year intervals gained 500 QALYs/100,000 at an incremental cost of $35,100/QALY gained but required 37% more colonoscopies. Over the ranges of parameters examined, the cost-effectiveness of hybrid screening strategies was slightly more sensitive to the adherence rate with colonoscopy than the adherence rate with yearly FIT. Uncertainties associated with estimates of FIT performance within a program setting and sensitivities for flat and right-sided lesions are expected to have significant impacts on the cost-effectiveness results. In our simulation model, a strategy of annual or biennial FIT, beginning when patients are 50 years old, with a single colonoscopy when they are 66 years old, delivers clinical and economic outcomes similar to those of CRC screening by single-modality strategies, with a favorable impact on resources demand.