To determine the cost-effectiveness of colorectal cancer screening strategies in Japan and to determine the influence of long-term compliance with screening programs on the selection of strategies, the natural history of a simulated cohort of 40-year-old Japanese of both genders was modeled with and without colorectal cancer screening until age 75 years. Survival, number of complications, and direct medical costs were compared among several combinations of screening examinations. In addition, the age of initiating screening was varied, as was the long-term compliance rate. Strategies using immunoiogical fecal occult blood test were found to be the most cost-effective. Immunological fecal occult blood test followed by colonoscopy, if positive, would save 24.05 (5.88 discounted) days of life and cost 28,420 yen (US $210) per screened person, thus offering a cost-effectiveness ratio of 1.765 million yen (US $13,100) per year of life saved. If long-term compliance is 100%, initiating screening at age 40 years offers more years of life saved and a low incremental cost of screening. However, if more likely dropout rates are considered, initiation at age 40 years is dominated by later initiation of screening.