Purpose: To estimate the cost-effectiveness of computed tomographic (CT) colonography for colorectal cancer (CRC) screening in average-risk asymptomatic subjects in the United States aged 50 years. Materials and Methods: Enrollees in the American College of Radiology Imaging Network National CT Colonography Trial provided informed consent, and approval was obtained from the institutional review board at each site. CT colonography performance estimates from the trial were incorporated into three Cancer Intervention and Surveillance Modeling Network CRC microsimulations. Simulated survival and lifetime costs for screening 50-year-old subjects in the United States with CT colonography every 5 or 10 years were compared with those for guideline-concordant screening with colonoscopy, flexible sigmoidoscopy plus either sensitive unrehydrated fecal occult blood testing (FOBT) or fecal immunochemical testing (FIT), and no screening. Perfect and reduced screening adherence scenarios were considered. Incremental cost-effectiveness and net health benefits were estimated from the U.S. health care sector perspective, assuming a 3% discount rate. Results: CT colonography at 5- and 10-year screening intervals was more costly and less effective than FOBT plus flexible sigmoidoscopy in all three models in both 100% and 50% adherence scenarios. Colonoscopy also was more costly and less effective than FOBT plus flexible sigmoidoscopy, except in the CRC-SPIN model assuming 100% adherence (incremental cost-effectiveness ratio: $26 300 per life-year gained). CT colonography at 5- and 10-year screening intervals and colonoscopy were net beneficial compared with no screening in all model scenarios. The 5-year screening interval was net beneficial over the 10-year interval except in the MISCAN model when assuming 100% adherence and willingness to pay $50 000 per life-year gained. Conclusion: All three models predict CT colonography to be more costly and less effective than non-CT colonographic screening but net beneficial compared with no screening given model assumptions.