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Most cost-effectiveness analyses of colorectal cancer (CRC) screening assume Medicare payment rates and a lifetime horizon. Our aims were to examine the implications of differential payment levels and time horizons for commercial insurers vs. Medicare on the cost-effectiveness of CRC screening.We used our validated Markov cohort simulation of CRC screening in the average risk US population to examine CRC screening at ages 50-64 under commercial insurance, and at ages 65-80 under Medicare, using a health-care sector perspective. Model outcomes included discounted quality-adjusted life-years (QALYs) and costs per person, and incremental cost/QALY gained.Lifetime costs/person were 20-44% higher when assuming commercial payment rates rather than Medicare rates for people under 65. Most of the substantial clinical benefit of screening at ages 50-64 was realized at ages ≥65. For commercial payers with a time horizon of ages 50-64, fecal occult blood testing (FOBT) and fecal immunochemical testing (FIT) were cost-effective (<$61,000/QALY gained), but colonoscopy was costly (>$185,000/QALY gained). Medicare experienced substantial clinical benefits and cost-savings from screening done at ages <65, even if screening was not continued. Among those previously screened, continuing FOBT and FIT under Medicare was cost-saving and continuing colonoscopy was highly cost-effective (<$30,000/QALY gained), and initiating any screening in those previously unscreened was highly effective and cost-saving.Modeling suggests that CRC screening is highly cost-effective over a lifetime even when considering higher payment rates by commercial payers vs. Medicare. Screening may appear relatively costly for commercial payers if only a time horizon of ages 50-64 is considered, but it is predicted to yield substantial clinical and economic benefits that accrue primarily at ages ≥65 under Medicare.