73 Background: Despite established screening guidelines, adherence to colonoscopy is approximately 60%. Blood-based screening tests, or Liquid Biopsies (LB), have the potential to close this screening gap. Our aim was to determine the cost-effectiveness of LB tests for CRC screening in the US. Methods: We developed a Markov model to compare four CRC screening strategies: no screening, or natural history (NH), colonoscopy (Colo) only, LB only, and colonoscopy to LB hybrid (C-LB). US SEER CRC incidence and mortality data were used to develop and validate the model. Many LB tests are in development awaiting validation; we used the preliminary performance characteristics for CRC screening of 82% sensitivity and 99.5% specificity (base case) from the Galleri multi-cancer early detection test (GRAIL). Screening ran from age 45 to 75; polyp surveillance ended at 85. We assumed 60.6% of the US population would undergo a screening colonoscopy, and 100% adherence for LB. In Colo, nonadherent patients were not offered other screening; in C-LB those who refused colonoscopy underwent LB. Primary outcomes were overall survival, total cost, incremental cost-effectiveness ratio (ICER), number of CRCs, and CRC deaths. Results: In the NH strategy, 5.2% of the population developed CRC and 1.8% died from CRC, with a cost of $7,802.15/individual. Compared to NH, in Colo, 40% of CRCs and 44% of CRC deaths were prevented, at a cost of $10,610.43/individual. In C-LB, 42% of CRCs and 50% of CRC deaths were prevented compared to NH, costing $13,762.61/individual. LB only prevented 2.0% of CRCs and 11% of CRC deaths compared to NH, and cost $34,339.85/individual. While LB showed an incremental benefit of 0.01 life years gained compared to NH, the ICER compared to NH is $2,653,770. Colo was most cost-effective with an ICER of $30,191.04. Although C-LB prevented the greatest number of CRCs, this strategy had an ICER of $457,057.64, above the accepted US willingness to pay threshold of $100,000/life year. We performed sensitivity analysis around base case estimates for LB. At both 70% and 90% test sensitivity, all outcomes remained largely constant. Conclusions: CRC screening with LB alone or with LB in conjunction with colonoscopy among nonadherent patients is not cost-effective in the US context. At this time, LB is unable to detect pre-cancerous colon polyps, which may limit its effectiveness as a CRC screening strategy. [Table: see text]