PURPOSE. Genomic screening for Lynch syndrome (LS) could prevent colorectal cancer (CRC) by identifying high-risk patients and instituting intensive CRC screening. We estimated the cost-effectiveness of population-wide LS genomic screening versus family history-based screening alone in an unselected U.S. population. METHODS. We developed a decision-analytic Markov model including health states for pre-cancer, stage-specific CRC, and death, and assumed an inexpensive test cost of $200. We conducted sensitivity and threshold analyses to evaluate model uncertainty. RESULTS. Screening unselected 30-year-olds for LS variants resulted in 48 (95% credible range [CR]: 35 to 63) fewer overall CRC cases per 100,000 screened individuals, leading to 187 quality-adjusted life-years (QALYs; 95% CR: 123 to 260) gained at an incremental cost of $24.6 million (95% CR: $20.3 million to $29.1 million). The incremental cost-effectiveness ratio was $132,200, with an 8% and 71% probability of being cost-effective at $100,000 and $150,000 per QALY willingness-to-pay thresholds, respectively. CONCLUSIONS. Population LS screening may be cost-effective in younger patient populations under a $150,000 willingness-to-pay per QALY threshold and with a relatively inexpensive test cost. Further reductions in testing costs and/or the inclusion of LS testing within a broader multiplex screening panel are needed for screening to be highly cost-effective.