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BACKGROUND The Centers for Disease Control and Prevention initiated the Colorectal Cancer Screening Demonstration Program (CRCSDP) to explore the feasibility of establishing a large-scale colorectal cancer (CRC) screening program for underserved populations in the United States. The authors of this report assessed the clinical costs incurred at each of the 5 participating sites during the demonstration period. METHODS By using data on payments to providers by each of the 5 CRCSDP sites, the authors estimated costs for specific clinical services and overall clinical costs for each of the 2 CRC screening methods used by the sites: colonoscopy and fecal occult blood test (FOBT). RESULTS Among CRCSDP clients who were at average risk for CRC and for whom complete cost data were available, 2131 were screened by FOBT, and 1888 were screened by colonoscopy. The total average clinical cost per individual screened by FOBT (including costs for screening, diagnosis, initial surveillance, office visits, and associated clinical services averaged across all individuals who received screening FOBT) ranged from $48 in Nebraska to $149 in Greater Seattle. This compared with an average clinical cost per individual for all services related to the colonoscopy screening ranging from $654 in St. Louis to $1600 in Baltimore City. CONCLUSIONS Variations in how sites contracted with providers and in the services provided through CRCSDP affected the cost of clinical services and the complexity of collecting cost data. Health officials may find these data useful in program planning and budgeting. Cancer 2013;119(15 suppl):2863-9. (c) 2013 American Cancer Society. By using data on payments to providers from each of the 5 Colorectal Cancer Screening Demonstration Program (CRCSDP) sites, the authors estimate costs for specific clinical services and overall clinical costs for each of the 2 colorectal cancer screening methods used: colonoscopy and fecal occult blood test. The results indicate that variations in how sites contracted with providers and in the services provided through the CRCSDP affected the cost of clinical services and the complexity of collecting cost data